Indazoles, benzisoxazoles and benzisothiazoles and their use as estrogenic agents

ABSTRACT

The present invention relates to compounds of formula (I): 
                         
in which R 1 , R 2 , R 3 , X, Y and A are as defined in the specification.
 
     The compounds are modulators of the estrogen receptors.

This application is a Continuation of U.S. application Ser. No.11/664,887, filed Jul. 30, 2007, which is a U.S. National Stage ofPCT/EP2005/055262, filed Oct. 14, 2005, which applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to non steroidal compounds with affinityfor estrogen receptors. More specifically, the invention relates toindazole, benzisoxazole and benzisothiazole compounds as estrogenreceptor subtype modulators and/or selective estrogen receptormodulators (SERM). The present invention also relates to pharmaceuticalcompositions containing these compounds, and to the use of thesecompounds in the treatment of estrogen-related diseases.

BACKGROUND OF THE INVENTION

The end of the reproductive years of a person's life can often beaccompanied by uncomfortable and disruptive symptoms, one of the mostcommon of which is hot flushes. Perimenopause, or premenopause, is theperiod of years in which normal ovulatory cycles give way to cessationof menses. This time is marked by irregular menstrual cycles. Cyclelength begins to increase, and ovulation and fertility decrease.Menopause is typically defined as the point, after the loss of ovarianactivity, when permanent cessation of menstruation occurs. In addition,estrogens are involved in various other physiological processes such asthe modulation of the immune response and development of cancer (breast,endometrium, colon, prostate). ERα has been proven to be implicated inseveral diseases, such as breast cancer, and osteoporosis. It is wellestablished that estrogens play an important role in the development andhomeostasis of the reproductive, central nervous, skeletal andcardiovascular systems in both males and females. To date, a plethora ofestrogen receptors have been discovered in the brain, involved invarious processes such as mood, temperature regulation, sleep,susceptibility to seizure, pain mechanism, and cognitive functions(Toran-Allerand, Endocrinology, 2004, 145, 1069-1074).

Currently, the estrogen receptor (ER) is a nuclear receptor with twoknown different subtypes. A new subtype ERβ, different from the knownERα subtype (Green, Nature, 1986, 320, 134-139), was recently discovered(Mosselman et al, FEBS Letters, 1996, 392, 49-53). These subtypes havedifferent biological roles and may have selective and effective clinicaluses (Harris H. A., Endocrinology, 2002, 143, 11, 4172-4177). ERsubtypes share about 50% identity in the ligand-binding domain (Kuiperet al, Endocrinology, 1998, 139(10), 4252-4263), they have similarEstradiol (E₂) binding affinities and can hetero- or homodimerize(Cowley, J Biol Chem, 1997, 272, 19858-19862) to form a signallingcomplex (Kuiper et al, Endocrinology, 1997, 138(10), 863-870; Kuiper,Proc. Natl. Acad. Sci. USA, 1996, 93, 5925-5930). ERβ is stronglyexpressed in a number of tissues including prostate epithelium (WeihuaZ, Proc. Natl. Acad. Sci. USA, 2001, 98, 6330-6335), sympathetic ganglia(Zoubina E. V., J. Urol., 2003, 169, 382-385), colon (Witte D., Hum.Pathol., 2001, 32, 940-944), bladder, ovarian granulosa cells (NilssonS., Physiol. Rev., 2001, 81, 1535-1565), bone marrow (Shim G. J., Proc.Natl. Acad. Sci. USA, 2003, 100, 6694-6699), breast stroma (Cunha G. R.,J. Mammary Gland Biol. Neoplasia, 1997, 2, 393-402), lung, intestine,vascular endothelium, dorsal raphe, parts of the brain (Mitra S. W.,Endocrinology, 2003, 144, 2055-2067, Krel W., Proc. Natl. Acad. Sci.USA, 2001, 98, 12278-12282). ERα is expressed in breast epithelium(Palmieri C., Endocr. Relat. Cancer, 2002, 9, 1-13), uterus, bone, ovarytheca cells (Couse J., Endocr. Rev., 1999, 20, 358-417), prostate stroma(Chu S., Mol. Cell Endocrinol., 1997, 132, 195-199), liver, testis. Thefinding of compounds with a specific affinity for one or the othersubtypes could provide a selective treatment of estrogen-relateddiseases such as Alzheimer's disease, menopausal complaints (e.g. hotflushes, vaginal dryness, atrophy), cognitive functions (e.g. anxiety,depression, dementia), osteoporosis, estrogen dependant tumours(uterine, breast, colon, or prostate cancers), benign prostatichyperplasia, bladder control, hearing disorders, stroke, leukaemia,hypertension, obesity, irritable bowel syndrome, or reproductive aspectssuch as contraception or infertility. ERβ-selective ligands may betherapeutically useful agents to treat chronic intestinal and jointinflammation (Harris et coll., Endocrinology, 2003, 144, 4241-4249).

According to Warembourg M and Leroy D (Brain Res., 2004, 26; 55-66), ERβwas only detected within the rat dorsal raphe nucleus. In contrast, onlyERα-immunoreactivity was seen in the septum, and in the magnocellularsupraoptic, paraventricular, arcuate, and premammillary nuclei. Theseobservations provide evidence of a distinct neuroanatomical pattern forthe two subtypes of the ERs. Localisation of ERβ in serotonin cells showthe link between ERβ and the serotoninergic pathway. Finally, Cyr M etal. described (J Psychiatry Neurosci., 2002, 27, 12-27) the effect of aselective estrogen receptor modulator (SERM) such as raloxifen on 5-HT2areceptor.

In conclusion it seems to be relevant to develop ERβ modulators ascompounds of interest in the field of schizophrenia, neurodegenerativediseases such a Alzheimer's disease or Parkinson's disease. For the samereasons, ERR modulators should be of interest as neuroprotective,antidepressant or anxiolytic agents.

However, the two receptors which act as ligand activated transcriptionfactors, were found in a variety of tissues, and differed in theirbinding pocket only by two amino acids: Leu and Met in ERα, Met and Ilein ERβ. Those similarities could explain that the control of the subtypealpha or beta led to the same pharmacological effect, as it is the casein preclinical model of hot flush phenomena. While ERα modulatordecreased the occurrence of hot flushes in a rat preclinical model(Harris et al., Endocrinology, 2002, 143, 4172-4177), selective estrogenreceptor modulators such as spiroindene compounds, which were affine forboth subtypes, had the same effect on hot flushes (Watanabe et al., JMed Chem, 2003, 46, 3961-3964).

It has also been shown that estrogen receptors can suppressNFKB-mediated transcription in both a ligand-dependent and independentmanner (Quaedackers, et al., Endocrinology 2001, 142: 1156-1166; Bhat,et al., Journal of Steroid Biochemistry & Molecular Biology 1998, 67:233-240; Pelzer, et al., Biochemical & Biophysical ResearchCommunications 2001, 286: 1153-7). These data show the link betweenselective estrogen receptor modulators and NFKB which is implicated inapoptosis and immune/inflammatory response.

Many compounds have been described as estrogen receptor agonists orantagonists as they respectively had a similar activity or blocked theactivity of estradiol. Such agonist compounds could be used ascontraceptive agents in premenopausal women. Antagonists are widely usedtherapeutic agents in the treatment of breast cancer (Vogel, AnticancerDrugs, 2003, 14, 265-273) whereas agonists are used in HRT (HormoneReplacement Therapy) in post menauposal women (Burkman, Minerva Ginecol,2003, 55, 107-116) to treat hot flushes, vaginal atrophy. SERMs arecompounds that present mixed activities depending on the tissue(McDonnell, J Soc Gynecol Invest, 2000, 7, S10-S15). SERMs might haveutility for the treatment of osteoporosis, cardiovascular diseases andrelated estrogen receptor diseases.

Estrogen receptors adopt different conformations when binding ligands.Three-dimensional structures of ERα and ERβ have been solved byco-crystallisation with various ligands (Pike A. C. W., EMBO 3, 1999,18, 4608-4618; Shiau A. K., Cell, 1998, 95, 927-937). Each ligandinfluences receptor ERα or ERβ conformations, leading to distinctbiological activities.

Various compounds presented as estrogenic agents have been described inUS 2003/0207927 A1 and US 2003/0171412 A1. Indazole derivativespresented as potassium channel blockers are described in WO 2004/043354and WO 2004/043933. The synthesis of various isoxazoles is described inInd J Chem 1980, 19B: 571-575. Benzisoxazole intermediates used in thepreparation of diuretic compounds are described in Chem Pharm Bull 1991,39(7): 1760-1772. The synthesis of various benzisothiazoles is describedin Tetrahedron 1988, 44(10): 2985-2992.

SUMMARY OF THE INVENTION

One aspect of this invention is to provide indazole, benzisoxazole andbenzisothiazole compounds, which have an affinity for the estrogenreceptors.

Another aspect of this invention is to provide a pharmaceuticalcomposition containing an indazole, benzisoxazole or benzisothiazolecompound as mentioned above.

A further aspect of this invention is to provide the use of an indazole,benzisoxazole, or benzisothiazole compound in the manufacture of amedicament for treating or preventing various diseases mediated byestrogen receptors.

The indazole, benzisoxazole or benzisothiazole compounds of thisinvention can be represented by the following general formula (I):

wherein:

-   -   R₁ is hydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,        trifluoromethyl, —N═CR₅R₆, —SO₂NR₇R₈, phenyl, phenyl(C₁-C₃)alkyl        or (C₁-C₃)alkyl substituted by a saturated heterocyclic radical,        wherein the phenyl is unsubstituted or substituted by at least        one substituent selected from the group consisting of a        hydroxyl, a halogen, a nitro, a cyano, a (C₁-C₃)alkyl, a        (C₁-C₃)alkoxy and a trifluoromethyl; R₁ can also be a salt;    -   R₂ and R₃ are each independently hydrogen or a hydroxyl,        halogen, nitro, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,        (C₁-C₆)alkoxy, trifluoromethyl, —NR₇R₈, —CONR₇R₈, —COR₉ or        —CO₂R₉ group; R₂ can also be a phenyl or a saturated or        unsaturated heterocycle, wherein the phenyl is unsubstituted or        substituted by at least one substituent selected from the group        consisting of a hydroxyl, a halogen, a nitro, a cyano, a        (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a trifluoromethyl and a saturated        heterocyclic radical;    -   X is O, S, SO, SO₂ or NR₄;    -   R₄ is hydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl,        phenyl(C₁-C₃)alkyl, (C₁-C₃)alkyl substituted by a saturated        heterocyclic radical, —COR₇, —CO₂R₇ or —SO₂NR₇R₈ group, wherein        the phenyl is unsubstituted or substituted by at least one        substituent selected from the group consisting of a hydroxyl, a        halogen, a nitro, a cyano, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a        trifluoromethyl, a phenyl(C₁-C₃)alkyl and a phenyl(C₁-C₃)alkoxy;    -   Y is direct bond, O, S, SO, SO₂, NR₄, CO, —(CR₁₀R₁₁)_(n)— or        —R₁₀C═CR₁₁—;    -   R₅, R₆, R₇ and R₈ are each independently hydrogen or a        (C₁-C₆)alkyl or (C₃-C₆)cycloalkyl group;    -   R₉ is hydrogen, a (C₁-C₆)alkyl, a phenyl or a saturated or        unsaturated heterocyclic radical, wherein the phenyl is        unsubstituted or substituted by at least one substituent        selected from the group consisting of a hydroxyl, a halogen, a        nitro, a cyano, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a        trifluoromethyl and a saturated heterocyclic radical;    -   R₁₀ and R₁₁ are each independently hydrogen or a cyano,        (C₁-C₆)alkyl, —CO-phenyl, —CO (unsaturated heterocyclic radical)        or —CONR₇R₈ group, wherein the phenyl is unsubstituted or        substituted by at least one substituent selected from the group        consisting of a hydroxyl, a halogen, a nitro, a cyano, a        (C₁-C₃)alkyl, a (C₁-C₃)alkoxy and a trifluoromethyl;    -   n is 1 or 2;    -   A is a (C₃-C₁₅)cycloalkyl, a (C₃-C₁₅)cycloalkene, a phenyl or a        naphthyl, wherein the cycloalkyl or the cycloalkene is        unsubstituted or substituted by at least one (C₁-C₆)alkyl, and        wherein the phenyl or the naphthyl is unsubstituted or        substituted by at least one substituent selected from the group        consisting of a hydroxyl, a halogen, a nitro, a cyano, a        (C₁-C₃)alkyl, a (C₁-C₃)alkoxy and a trifluoromethyl;    -   when X is NR₄, Y and R₂ together with the indazole ring bearing        them can also form a 1H-pyrano[4,3,2-cd]indazole.

The compounds of formula (I) are claimed as such except that:

1/ when X is O, S or NR₄, R₁ is hydrogen or a (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl or trifluoromethyl, and Y is a direct bond, then A isnot optionally substituted phenyl or optionally substituted naphthyl;

2/ when X is NR₄ where R₄ is H or (C₁-C₆)alkyl and R₁O is 6-OCH₃, then Yis not CO;

3/ when X is O, R₁O is 6-OH or 6-OCH₃, Y is a direct bond and A iscyclopentyl, then (R₂,R₃) or (R₃,R₂) is different from (H, Cl) inposition 4,5;

4/ when X is O, R₁O is 6-OH, R₂ and R₃ are H and Y is CH═CH, then A isnot phenyl or 4-methoxyphenyl;

5/ When X is SO₂, A is phenyl and R₁O is 5- or 6-OCH₃, then (R₂,R₃) or(R₃,R₂) is different from (H, OCH₃) in position 6- or 5-.

In the description and claims, the term “(C₁-C₆)alkyl” is understood asmeaning a linear or branched hydrocarbon chain having 1 to 6 carbonatoms. A (C₁-C₆)alkyl radical is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexylradical. Preferred alkyl radicals are those having 1, 2 or 3 carbonatoms.

The term “halogen” is understood as meaning a chlorine, bromine, iodineor fluorine atom.

The term “(C₃-C₁₅)cycloalkyl” is understood as meaning a saturated,fused or bridged, mono-, bi- or tricyclic hydrocarbon having 3 to 15carbon atoms. A monocyclic radical is for example a cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclododecylradical. A fused, bridged or spiranic, dicyclic or tricyclic radical isfor example a norbornyl, bornyl, isobornyl, noradamantyl, adamantyl orspiro[5,5]undecanyl radical. Preferred cycloalkyls are those having 5 to12 carbon atoms, the cyclopentyl, cyclohexyl, cycloheptyl and adamantylradicals being especially preferred. A (C₃-C₆)cycloalkyl radical is forexample a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

The term “(C₃-C₁₅)cycloalkene” is understood as meaning an unsaturated(C₃-C₁₅)cycloalkyl, the latter term being as defined above.

The term “(C₁-C₆)alkoxy” is understood as meaning a group OR in which Ris a (C₁-C₆)alkyl as defined above. A (C₁-C₆)alkoxy radical is forexample a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, n-pentyloxy or isopentyloxy radical. Preferred alkoxyradicals are those having 1, 2 or 3 carbon atoms.

In the definition of R₁, a “salt” is understood as meaning an alkalimetal salt or alkaline earth metal salt, such as a sodium, potassium,magnesium or calcium salt, or a salt with an ammonium or with an organicamine such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.

The term “heterocycle” or “heterocyclic”, is understood as meaning asaturated or unsaturated 5- to 8-membered monocyclic radical containingone or two heteroatoms chosen from O, N and S.

Examples of unsaturated heterocyclic radicals include, but are notlimited to, the furyl, imidazolinyl, imidazolyl, pyridyl, pyrazinyl,pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,isoquinolinyl, thiazolyl, thienyl benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl and indazolyl radicals.

Examples of saturated heterocyclic radicals include, but are not limitedto, the imidazolidinyl, morpholinyl, thiomorpholinyl, piperidyl,piperazinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl,2-oxopiperazinyl, 2-oxopiperidyl and 2-oxopyrrolidinyl radicals, themorpholinyl and piperidyl radicals being preferred.

Needless to say, when X is NR₄ and Y and R₂ together form with theindazole ring bearing form a 1H-pyrano[4,3,2-cd]-indazole, one of thecarbon atom of the “pyrano moiety” bears substituent A as defined above.

The compounds of formula (I) can form addition salts with acids. Suchsalts, especially those which are pharmaceutically acceptable, areencompassed by the present invention. Examples of salts include thoseformed, for example with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or withorganic carboxylic acids such as acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid.

The present invention also encompasses stereoisomeric forms of thecompounds of formula (I).

Preferred compounds of formula (I) include those that fulfil at leastone of the following conditions:

-   -   R₁ is hydrogen, a (C₁-C₆)alkyl, a phenyl(C₁-C₃)alkyl, a        (C₁-C₃)alkyl substituted by a saturated heterocyclic radical or        a —SO₂NR₇R₈ group;    -   R₂ is hydrogen, hydroxyl, (C₁-C₆)alkyl or halogen;    -   R₃ is hydrogen;    -   Y is direct bond;    -   A is a (C₃-C₁₅)cycloalkyl optionally substituted by at least one        (C₁-C₆)alkyl;    -   R₁O is in position 6- of the ring.

Particularly preferred compounds are those wherein:

-   -   R₁ is hydrogen or a —SO₂NR₇R₈ group in which R₇ and R₈ are each        independently hydrogen or a (C₁-C₆)alkyl;    -   R₂ is hydrogen;    -   A is a (C₃-C₁₂)cycloalkyl optionally substituted by 1 to 4        (C₁-C₆)alkyls.

The following compounds are also preferred:

a) Compounds where X is NR₄ and

-   -   R₁ is hydrogen or a (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl or        —SO₂NR₇R₈ group;    -   R₂ and R₃ are each hydrogen;    -   R₄ is hydrogen or a (C₁-C₆)alkyl, phenyl, phenyl(C₁-C₃)alkyl,        (C₁-C₃)alkyl substituted by a saturated heterocyclic radical,        —SO₂NR₇R₈ or —COR₉ group, where the phenyl is optionally        substituted by at least one substituent selected from the group        consisting of a hydroxyl, a halogen and a phenyl(C₁-C₃)alkoxy;    -   Y is a direct bond, —(CR₁₀R₁₁)_(n)— or —R₁₀C═CR₁₁;    -   R₇ and R₈ are each independently hydrogen or a (C₁-C₆)alkyl;    -   R₉ is hydrogen or a (C₁-C₆)alkyl;    -   R₁₀ and R₁₁ are each independently hydrogen, cyano or a —CONR₇R₈        group;    -   n is 1 or 2;    -   A is a (C₃-C₁₅)cycloalkyl optionally substituted by at least one        (C₁-C₆)alkyl or a phenyl optionally substituted by a hydroxyl or        a (C₁-C₃)alkoxy;    -   Y and R₂ together with the indazole ring bearing them can also        form a 1H-pyrano[4,3,2-cd]indazole;        provided that when R₁ is H or (C₁-C₆)alkyl and Y is a direct        bond, then A is not optionally substituted phenyl.        b) Compounds where X is O and    -   R₁ is hydrogen or a (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl,        (C₁-C₃)alkyl substituted by a saturated heterocyclic radical or        —SO₂NR₇R₈ group;    -   R₂ is hydrogen, halogen, hydroxyl or (C₁-C₆)alkoxy;    -   R₃ is hydrogen;    -   Y is a direct bond, —(CR₁₀R₁₁)_(n) or —CR₁₀═CR₁₁—;    -   R₇ and R₈ are each independently hydrogen or (C₁-C₆)alkyl;    -   R₁₀ and R₁₁ are each independently hydrogen or cyano;    -   n is 1 or 2;    -   A is a (C₃-C_(1s))cycloalkyl optionally substituted by at least        one (C₁-C₆)alkyl or a phenyl optionally substituted by at least        one substituent selected from (C₁-C₃)alkoxy, hydroxyl,        (C₁-C₃)alkyl and halogen;        provided that        b1/ when R₁ is H or (C₁-C₆)alkyl and Y is a direct bond, then A        is not optionally substituted phenyl;        b2/ when R₁O is 6-OH or 6-OCH₃, Y is a direct bond and A is        cyclopentyl, then (R₂,R₃) is different from (Cl, H) in position        4,5;        b3/ when X is O, R₁O is 6-OH, R₂ and R₃ are H and Y is CH═CH,        then A is not phenyl or 4-methoxyphenyl;        c) Compounds where X is S(O)_(m) and    -   R₁ is hydrogen or a phenyl(C₁-C₃)alkyl or —SO₂NR₇R₈ group;    -   R₂ and R₃ are each hydrogen, hydroxyl or halogen;    -   Y is a direct bond, —(CR₁₀R₁₁)_(n) or —CR₁₀═CR₁₁—;    -   R₇ and R₈ are each independently hydrogen or a (C₁-C₆)alkyl;    -   R₁₀ and R₁₁ are each independently hydrogen or cyano;    -   A is a (C₃-C₁₅)cycloalkyl optionally substituted by at least one        (C₁-C₆)alkyl;    -   m is 0, 1 or 2.

In view of their capability to act as agonists or antagonist forestrogen receptors (in other words as SERMs), the compounds of theinvention can be used alone or in combination with other activeingredients for the treatment or the prevention of anyestrogen-dependent disorder or for the management of estrogen-regulatedreproductive functions, in humans (Njar V C and Brodie A M, Drugs, 1999,58: 233-255) as well as, in wild or domestic animals.

The breasts being sensitive targets of estrogen-stimulated proliferationand/or differentiation, SERMs are especially useful in the treatment orprevention of benign breast diseases in women, gynecomastia in men andin benign or malignant breast tumors with or without metastasis both inmen and women (A. M. Brodie and V. C. Njar, Steroids, 2000, 65: 171-179;K. I. Pritchard, Cancer, 2000, 85, suppl 12: 3065-3072), or in male orfemale domestic animals.

Due to the involvement of estrogens in the mechanisms of ovulation,implantation and pregnancy, SERMs according to the invention can beused, respectively, for contraceptive, contragestive or abortivepurposes in women (A. M. Brodie and V. C. Njar, Drugs, 1999, 58:233-255) as well as in females of wild or domestic animal species.

The uterus is another reproductive organ responsive to estrogenicstimulation. SERMs are therefore useful to treat or preventendometriosis, benign uterine diseases or benign or malignant uterinetumors with or without metastasis in women (A. M. Brodie and V. C. Njar,Drugs, 1999, 58: 233-255) or in female domestic animals.

The ovary being the physiological source of estrogen, SERMs can be usedto treat abnormal or untimely ovarian estrogen production such aspolycystic ovary syndrome or precocious puberty, respectively (Bulun etal., 3 Steroid Biochem Mol Biol, 1997, 61: 133-139). Ovarian as well asnon-ovarian but estrogen-producing benign or malignant tumors with orwithout metastasis (Sasano H and Harada N, Endocrine Reviews, 1998, 19:593-607) may also benefit from treatment with SERMs according to theinvention.

In males, prostate and testicular tissues are also responsive toestrogenic stimulation (Abney T O, Steroids, 1999, 64: 610-617; CarreauS et al., Int J Androl, 1999, 22: 133-138). Therefore, SERMs can be usedto treat or to prevent benign (Sciarra F and Toscano V, Archiv Androl,2000, 44: 213-220) or malignant prostate tumors with or withoutmetastasis (Auclerc G et al., Oncologist, 2000, 5: 36-44) or to treat,prevent or control spermatogenesis functions or malfunctions, in men aswell as in male wild or domestic animals.

Estrogens are also known to be implicated in the regulation of boneturnover; therefore, SERMs may be useful, alone or in combination withother antiresorbtive or proosteogenic agents, in the treatment orprevention of bone disorders according to appropriate therapeuticsequences or regimens.

In addition, estrogens are involved in the regulation of the balancebetween Th₁ and Th₂ predominant immune functions and may therefore beuseful in the treatment or prevention of gender-dependent auto-immunediseases such as lupus, multiple sclerosis, rheumatoid arthritis.

Another aspect of the invention thus consists in a method for thetreatment or prevention of the above-mentioned diseases or disorders,wherein a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof is administered to apatient or animal in need of such treatment or prevention.Co-administration with one or more active substances suitable for thetreatment or prevention of said diseases or disorders is alsoencompassed by the present invention.

The compounds of the invention can in particular be used in thefollowing indications:

-   -   treatment of cognitive dysfunction, for instance as        neuroprotective, antidepressant or anxiolytic agents.    -   treatment of schizophrenia or neurodegenerative diseases such as        Alzheimer's disease or Parkinson's disease.    -   prevention or treatment of estrogen-dependent disorders, for        example hot flushes, osteoporosis, perimenopausal mood,        perimenstrual syndromes, vasomotor related syndromes, vaginal        atrophy or dryness, sexual dysfunction such as libido decrease,        urinary incontinence, pruritus, local infections of the genital        tract. In this case, said compounds can be combined with a        sexual endocrine therapeutic agent.    -   control or management of reproductive functions, such as male or        female fertility, pregnancy, abortion, contraception, delivery,        or estrogen-related skin diseases. In this case, said compounds        can be combined with a LH-RH agonist or antagonist, an        estroprogestative contraceptive, a progestin, an antiprogestin        or a prostaglandin.    -   prevention or treatment of benign or malignant diseases of the        breast, the uterus or the ovary, or of polycystic ovary        syndrome. In this case, said compounds can be combined with an        antiestrogen, a progestin or a LH-RH agonist or antagonist.    -   prevention or treatment of benign or malignant diseases of the        prostate or the testis. In this case, said compounds can be        combined with an antiandrogen, a progestin, a lyase inhibitor or        a LH-RH agonist. If necessary, the compounds of the invention        can also be combined with a radiotherapeutic agent; a        chemiotherapeutic agent such as a nitrogenated mustard analogue        like cyclophosphamide, melphalan, iphosphamide, or        trophosphamide; an ethylenimine like thiotepa; a nitrosourea        like carmustine; a lysed agent like temozolomide or dacarbazine;        an antimetabolite of folic acid like methotrexate or        raltitrexed; a purine analogue like thioguanine, cladribine or        fludarabine; a pyrimidine analogue like fluorouracil, tegafur or        gemcitabine; an alkaloid of vinca or analogue like vinblastine,        vincristine or vinorelbine; a podophyllotoxin derivative like        etoposide, taxanes, docetaxel or paclitaxel; an anthracycline or        analogue like doxorubicin, epirubicin, idarubicin or        mitoxantrone; a cytotoxic antibiotic like bleomycin or        mitomycin; a platinum compound like cisplatin, carboplatin or        oxaliplatin; a monoclonal antibody like rituximab; an        antineoplastic agent like pentostatin, miltefosine,        estramustine, topotecan, irinotecan or bicalutamide; or with a        prostaglandin inhibitor (COX 2/COX 1 inhibitor).    -   prevention or treatment of irritable bowel syndrome, Crohn's        disease, ulcerative proctitis, colitis or arthritis.    -   prevention or treatment of cardiovascular diseases,        atherosclerosis, hypertension, restenosis (e.g. for lowering        cholesterol, triglycerides, Lp(a), or LDL levels, or modulating        HDL level).

As used herein, the term “combined” or “combination” refers to anyprotocol for the co-administration of a compound of formula (I) and oneor more other pharmaceutical substances, irrespective of the nature ofthe time of administration and the variation of dose over time of any ofthe substances. The co-administration can for example be parallel,sequential or over an extended period of time.

The compounds of formula (I) or their pharmaceutically acceptable saltsmay be administered, for example, orally, topically, parenterally, indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and/or vehicles. Thesedosage forms are given as examples, but other dosage forms may bedeveloped by those skilled in the art of formulation, for theadministration of the compounds of formula (I). The term parenteral asused herein includes subcutaneous injections, intravenous, intramuscularor intrasternal injections or infusion techniques. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattlesheep, dogs, cats, etc., the compounds of the invention are effective inthe treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known inthe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients, whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inU.S. Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Aqueous suspensions contain the active ingredient in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those mentionedabove, and flavoring agents may be added to provide a palatable oralpreparation.

These compositions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. The pharmaceutical compositions of theinvention may also be in the form of an oil-in-water emulsion. The oilyphase may be a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. Suitableemulsifying agents include naturally-occurring phosphatides, for examplesoy bean, lecithin, and esters or partial esters derived from fattyacids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Acceptablevehicles and solvents that may be employed include water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Dosage levels of the order of from about 0.001 mg to about 10 mg/kg ofbody weight per day are useful in the treatment or prevention of theabove-mentioned diseases or disorders, or alternatively about 0.1 mg toabout 100 mg per patient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The indazole derivatives of formula (I) can be prepared according togeneral schemes Ia, Ib, Ic.

According to scheme Ia fluoroanisole derivative (1) is reacted with asuitable acid chloride of formula (2) by Friedel-Craft reactionfollowing the procedure described by K L Kees (J Med Chem, 29, 11, 1986,2329-2334) to give ketone (5). This ketone (5) can also be obtained bycondensation of alkylmagnesium (4) on fluorobenzonitrile derivative (3)according to H. Shaffer (J Am Chem Soc, 1939, 61, 2175). The ketone (5)is then refluxed in EtOH in the presence of substituted hydrazine or inhydrazine hydrate to afford respectively the cyclised indazoles (6) and(7). The compound (7) can also be prepared by selective N-alkylation ofindazole (6) using the conditions described by U. Lerch and J. König(Synthesis, 1983, 2, 157-8) or the conditions described by J Chung andall (Tetrahedron Letters, 1992, 33, 4717-20).

Demethylation of compounds (6) and (7) (if R₁ is methyl) with eithertribromoborane using the conditions described by J. F. W. McOmie(Tetrahedron, 1968, 24, 2289-92) or HBr/AcOH or pyridinium hydrochlorideor debenzylation of compounds (6) and (7) (if R₁ is benzyl) with Pd/Cwith or without PtO₂ using the conditions described by W. H. Hartung(Org. React., VII, 1953, 263) give respectively the hydroxy indazolecompounds (8) and (12). Indazole (6) can be directly N-sulfamoylated togive (10) by treatment with sodium hydride and sulfamoyl chloride asdescribed by P. Nussbaumer (J. Med. Chem., 2002, 45, 4310-20), or byreaction with sulfamoyl chloride in dimethylacetamide (DMAc) asdescribed by O. Makoto (Tetrahedron Letters, 2000, 41, 7047-51), thendeprotected to obtain sulfamate compound (II). Deprotected indazole (8)can be disulfamoylated to give (9). In the same way, indazole (12) canbe reacted with sulfamoyl chloride to give O-sulfamate compound (13) andthen deprotected to give (14).

According to scheme Ib, the 3-methyl indazole compound (15) preparedusing the conditions described by F. Dennier (Tetrahedron, 22, 1966,3131) was reacted with BOC₂O, TEA and DMAP (T. Ishizuki, TetrahedronLett., 28, 1987, 4185) to afford (16). Compound (16) was brominated byWohl-Ziegler reaction in presence of NBS and benzoyl peroxide followingB. R. Henke (J. Med. Chem., 1997, 40, 17, 2706-2725) to give (17).Compound (18) was obtained by reaction of (17) with KCN using theconditions described by Ainsworth (J. Am. Chem. Soc., 1957, 79,5242-5243). (18) was then reacted with aldehyde (19) in NaH/DMF orKOH/EtOH to give (20) following the procedure described by M. J. Meyers(J. Med. Chem., 44, 24, 2001, 4230) (BOC deprotection was performedduring this reaction). Compound (20) was then reacted with NaBH₄ in EtOHto give (21). Demethylation of compound (21) (if R₁ is methyl) witheither tribromoborane using the conditions described by J. F. W. McOmie(Tetrahedron, 1968, 24, 2289-92) or HBr/AcOH or pyridinium hydrochlorideor debenzylation of compound (21) (if R₁ is benzyl) with Pd/C with orwithout PtO₂ using the conditions described by W. H. Hartung (Org.React., VII, 1953, 263) gave nitrile compound (22). Demethylation withHBr/AcOH gave amide compound (23).

According to scheme Ic, compound (24), prepared using the conditionsdescribed by M. Kitagawa (Chem. Pharm. Bull., 39, 10, 1991, 2681), wasreacted with hydrazine hydrate or alkyl or aryl hydrazine under refluxto give compound (25). Compound (25) was demethylated in the presence ofBBr₃ in CH₂Cl₂ using the conditions described by McOmie J. F. W(Tetrahedron, 1968, 24, 2289-92) to give compounds (26) and (27).

The benzisoxazole derivatives of formula (I) can be prepared accordingto general schemes IIa, IIb, IIc.

According to scheme IIa, the already described ketone (5) or ketone (29)obtained by Friedel-Craft procedure described by K L Kees (3 Med Chem,29, 11, 1986, 2329-2334) are refluxed in hydroxylamine hydrochlorideusing the conditions described by Y. Yamanaka (Pestic. Sci., 1998, 54,3, 223-229) to afford respectively uncyclised oxime (28) and (30).Compound (28) is then cyclised in refluxing NaOH/EtOH solution andcompound (30) is cyclised using an intramolecular Mitsunobu reaction(Synthesis, 1981, 1) to afford the corresponding benzisoxazole (31).

Demethylation of compound (31) (if R₁ is methyl) with eithertribromoborane using the conditions described by J. F. W. McOmie(Tetrahedron, 1968, 24, 2289-92) or HBr/AcOH or pyridinium hydrochlorideor debenzylation of compounds (31) (if R₁ is benzyl) with Pd/C usingconditions described by A. M. Felix (3. Org. Chem., 43, 1978, 4194) givethe hydroxy benzisoxazole compound (32). This compound (32) can betransformed into the corresponding sulfamate (33) by treatment withsodium hydride and sulfamoyl chloride (P. Nussbaumer., J. Med. Chem.,2002, 45, 4310-20), or by reaction with sulfamoyl chloride indimethylacetamide (DMAc) (O. Makoto, Tetrahedron letters, 2000, 41,7047-51). Compound (32) can also be transformed into ether compound (34)by reaction with 1-(2-chloroethyl)piperidine using conditions describedby M. R. Tremblay (Bioorg. Med. Chem., 1999, 7, 6, 1013-1024).

According to scheme IIb the benzisoxazole (35) prepared using theconditions described by H. Uno (Chem. Pharm. Bull., 24, 1976, 632) wasreacted with aldehyde (19) in NaH/DMF or KOH/EtOH to give (36). Compound(36) was reacted with NaBH₄ in EtOH to give (37).

Demethylation of compound (37) with either tribromoborane using theconditions described by J. F. W. McOmie (Tetrahedron, 1968, 24, 2289-92)or HBr/AcOH or pyridinium hydrochloride gave the hydroxy benzisoxazolecompound (38).

According to scheme IIc the benzisoxazole (39) prepared using theconditions described by M. A. Elkasaby (Indian J. Chem. Sect B, 1980,19, 571) was protected with tea-butyldimethylsilylchloride inimidazole/DMF (P. M. Kendall, J. Org. Chem., 44, 1979, 1421) and thecompound (40) obtained was brominated in the presence of NBS and benzoylperoxide to give (41). Compound (41) was reacted with LDA andsubstituted phenylacetonitrile to give (42) using the proceduredescribed by E. Teodori (Bioorg. Med. Chem., 7, 9, 1999, 1873-1880).Deprotection of the hydroxyl group in presence of nBu₄F using theconditions described by E. J. Corey (J. Am. Chem. Soc., 94, 1972, 6190)gave compound (43).

The benzisothiazole derivatives of formula (I) can be prepared accordingto general scheme III.

According to scheme III, ketone (5) was reacted with phenylmethanethiolto give (44). The obtained compound (44) was refluxed in sulfurylchloride followed by ammoniac treatment to afford cyclisedbenzisothiazole (45) according to the procedure described by D. M. Fink(Tetrahedron Letters, 1993, 34, 41, 6525-6528). Demethylation ofcompounds (45) with either tribromoborane using the conditions describedby J. F. W McOmie (Tetrahedron, 1968, 24, 2289-92) or HBr/AcOH orpyridinium hydrochloride gave the hydroxy benzisothiazole compounds(46). These compounds (46) can be transformed into the correspondingsulfamates (47) by treatment with sodium hydride and sulfamoyl chloride(P. Nussbaumer, J. Med. Chem., 2002, 45, 4310-20), or by reaction withsulfamoyl chloride in dimethylacetamide (DMAc) (O. Makoto. Tetrahedronletters, 2000, 41, 7047-51).

Oxidation of these compounds (46) and (47) by hydrogen peroxide intrifluoroacetic acid, following the conditions described by S. Grivasand E. Ronne (Acta Chemica Scandinavia, 1995, 49, 225-229), gaverespectively the mono and/or dioxidised benzisothiazoles (49) and (48).Compound (49) can be sulfamoylated to give (48). General schemes I, IIand III illustrate the synthesis of compounds (I) in which thesubstituent R₁O is in position 6- of the heterocyclic ring. It willhowever be appreciated that compounds (I) where the substituent R₁₀ isin position 4-, 5- or 7- of the heterocyclic ring can be prepared usingthe procedures described above.

The following examples are intended to illustrate and not to limit thescope of the invention.

Preparation of Acetophenones (5) EXAMPLE 14-benzyloxy-2-fluorobenzonitrile

To a mixture of 2-fluoro-4-hydroxy-benzonitrile (98 g, 0.68 mol) andK₂CO₃ (94 g, 0.68 mol) in acetonitrile was added benzyl chloride (86.6g, 0.68 mol). The mixture was stirred overnight at room temperature andthe reaction followed by TLC (toluene/AcOEt 8/2). The mixture wasfiltered, concentrated under vacuum and crystallized from pentane togive 147 g of solid (95%).

¹H-NMR (DMSO d₆): 5.25 (s, 2H), 7.05 (dd, 1H), 7.25 (dd, 1H), 7.30-7.60(m, 5H), 7.75 (t, 1H).

Using the same procedure but replacing 2-fluoro-4-hydroxy-benzonitrileby:

-   cycloheptyl (2-fluoro-4-hydroxyphenyl)methanone-   1-adamantyl (2-fluoro-4-hydroxyphenyl)methanone    the following compounds were respectively obtained:

EXAMPLE 2 cycloheptyl (4-benzyloxy-2-fluorophenyl)methanone

(71%).

¹H-RMN (CDCl₃): 1.10-2.00 (m, 12H), 3.50 (m, 1H), 5.17 (s, 2H), 6.85(dt, 1H), 7.20 (dd, 1H), 7.30-7.60 (m, 6H).

EXAMPLE 3 1-adamantyl (4-benzyloxy-2-fluorophenyl)methanone (38%)

¹H-NMR (DMSO d₆): 1.30-2.30 (m, 15H), 5.20 (s, 2H), 6.85 (dt, 1H), 7.12(dd, 1H), 7.20-7.60 (m, 6H).

EXAMPLE 4 cyclopentyl (4-benzyloxy-2-fluorophenyl)methanone

A suspension of magnesium (19 g, 0.79 mol) and iodine (catalytic amount)in THF (20 ml) was refluxed under N₂. A solution of cyclopentylbromide(110 g, 0.738 mol) in THF (400 ml) was added slowly. The mixture wasrefluxed until all the magnesium was consumed, then cooled to 30° C. andadded to a solution of 4-benzyloxy-2-fluorobenzonitrile (129 g, 0.56mol) in THF (600 ml). The reaction was stirred at 50° C. overnight thenquenched by aqueous NH₄Cl and ice, extracted with ethyl acetate, andwashed with brine. The mixture was dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by flash chromatography(heptane/EtOAc 9/1) gave 60 g of product (35%, as solid).

¹H-NMR (DMSO d₆): 1.40-2.00 (m, 8H), 3.58 (m, 1H), 5.20 (s, 2H),6.85-7.20 (m, 2H), 7.25-7.55 (m, 5H), 7.80 (t, 1H).

Using the same procedure but replacing cyclopentylbromide bycyclohexylchloride, the following compound was obtained:

EXAMPLE 5 cyclohexyl (4-benzyloxy-2-fluorophenyl)methanone

(35%). mp 78° C.

¹H-NMR (DMSO d₆): 1.00 to 2.00 (m, 10H), 3.05 (m, 1H), 5.20 (s, 2H),6.90-7.10 (m, 2H), 7.20-7.60 (m, 5H), 7.75 (t, 1H).

EXAMPLE 6 1-adamantyl (2-fluoro-4-hydroxyphenyl)methanone

To a mixture of AlCl₃ (45 g, 0.337 mol) in 1,2-dichloroethane (DCE, 250ml) at 0° C. was added 1-adamantyl carbonyl chloride (36.6 g, 0.228 mol)in DCE (150 ml). 3-fluorophenol (21 g, 0.183 mol) in DCE (100 ml) wasadded slowly at 0° C. The reaction was followed by TLC (heptane/toluene50/50). The mixture was poured onto HCl 2N, extracted with AcOEt, washedwith Nat-HCO₃ and brine, dried over Na₂SO₄, filtered and concentratedunder vacuum. Purification by flash chromatography (heptane/toluene 8/2)gave 27 g of 1-adamantyl (2-fluoro-4-hydroxyphenyl)methanone (48% assolid).

¹H-NMR (DMSO, d₆): 1.30 (m, 15H), 5.97 (s, 1H), 6.70 (d, 1H), 6.94 (dd,1H), 7.64 (d, 1H).

Using the same procedure but replacing 1-adamantyl carbonyl chloride bycycloheptane carbonyl chloride, the following compound was obtained:

EXAMPLE 7 cycloheptyl (2-fluoro-4-hydroxyphenyl)methanone

(60%).

¹H-RMN (CDCl₃): 1.20-2.00 (m, 12H), 3.58 (m, 1H), 6.70-6.90 (m, 2H),7.90-8.10 (m, 1H), 12.45 (s, 1H).

Using the same procedure but replacing 1-adamantyl carbonyl chloride bycycloheptane carbonyl chloride and 3-fluorophenol by 3-fluoroanisole,the following compound was obtained:

EXAMPLE 8 cycloheptyl (4-methoxy-2-fluorophenyl)methanone

(45%).

¹H-NMR (CDCl₃): 1.40-2.00 (m, 12H), 1.9 (3, 2H), 3.25 (m, 1H), 3.80 (s,3H), 6.50 (dd, 1H), 6.65 (dd, 1H), 7.75 (t, 1H).

Using the same procedure but replacing 3-fluorophenol by:

-   3-fluoroanisole-   3,5-dimethoxy-chlorobenzene    the following compounds were respectively obtained:

EXAMPLE 9 1-adamantyl (4-methoxy-2-fluorophenyl)methanone

(15%).

¹H-NMR (CDCl₃): 1.50-2.30 (m, 15H), 3.85 (s, 3H), 6.60 (2d, 1H), 6.70(2d, 1H), 7.70 (t, 1H).

EXAMPLE 10 1-adamantyl (2-chloro-4,6-dimethoxyphenyl)methanone (22%)

¹H-NMR (CDCl₃, d₁): 1.60-2.10 (m, 15H), 3.75 (s, 3H), 3.80 (s, 3H), 6.35(s, 1H), 6.50 (s, 1H).

Using the same procedure but replacing 3-fluorophenol by 3,4-dimethoxyfluorobenzene and 1-adamantyl carbonyl chloride by cyclohexane carbonylchloride, the following compound was obtained:

EXAMPLE 11 cyclohexyl (2-fluoro-4-hydroxy-5-methoxyphenyl)methanone

¹H-NMR (DMSO, d₆): 1.00-2.00 (m, 10H), 3.05 (m, 1H), 3.80 (s, 3H), 6.65(d, 1H), 7.23 (d, 1H), 10.50 (s, 1H).

Preparation of Indazoles (6), (7), (8) and (12) EXAMPLE 126-benzyloxy-3-cyclopentyl-1H-indazole

A mixture of cyclopentyl (4-benzyloxy-2-fluorophenyl)methanone (40 g,0.13 mol) in hydrazine hydrate (50 ml) was refluxed overnight. Aftercooling to room temperature, the solid was filtered, dissolved in EtOAc,then washed with aqueous NH₄Cl and brine. The solution was dried overNa₂SO₄, filtered and concentrated under vacuum. Purification by flashchromatography (toluene/EtOAc 9/1) gave the expected product (13 g, 45%as solid).

¹H-NMR (DMSO d₆): 1.40-2.20 (m, 8H), 3.34 (m, 1H), 5.13 (s, 2H), 6.75(dd, 1H), 6.90 (d, 1H), 7.20-7.53 (m, 5H), 7.57 (d, 1H), 9.40 (s, 1H).

Using the same procedure but replacing cyclopentyl(4-benzyloxy-2-fluorophenyl)methanone by:

-   cyclohexyl (4-benzyloxy-2-fluorophenyl)methanone-   cycloheptyl (4-benzyloxy-2-fluorophenyl)methanone-   1-adamantyl (4-methoxy-2-fluorophenyl)methanone-   cycloheptyl (4-methoxy-2-fluorophenyl)methanone    the following compounds were respectively obtained:

EXAMPLE 13 6-benzyloxy-3-cyclohexyl-1H-indazole

(58%).

¹H-RMN (CDCl₃): 1.10-2.10 (m, 10H), 2.95 (m, 1H), 5.15 (s, 2H), 6.75(dd, 1H), 6.90 (d, 1H), 7.20-7.55 (m, 5H), 7.65 (d, 1H), 12.32 (s, 1H).

EXAMPLE 14 6-benzyloxy-3-cycloheptyl-1H-indazole

(85%).

¹H-RMN (CDCl₃): 1.20-2.10 (m, 12H), 2.55 (m, 1H), 5.07 (s, 2H), 6.45(dd, 1H), 6.55 (d, 1H), 6.95 (d, 1H), 7.20-7.50 (m, 5H).

EXAMPLE 15 3-(1-adamantyl)-6-methoxy-1H-indazole

(30%).

¹H-NMR (CDCl₃): 1.50-2.70 (m, 15H), 3.85 (s, 3H), 6.78 (dd, 1H), 6.88(d, 1H), 7.57 (d, 1H)

EXAMPLE 16 3-cycloheptyl-6-methoxy-1H-indazole

(45%).

¹H-NMR (CDCl₃): 1.40-2.30 (m, 12H), 3.22 (m, 1H), 3.83 (s, 3H), 6.35 (s,1H), 6.65-6.90 (m, 2H), 7.58 (d, 1H).

Using the same procedure but replacing hydrazine hydrate by1-(4-benzyloxyphenyl)hydrazine (prepared following K. J. Duffy, 3 MedChem 2001, 44, 22, 3730-3745), the following compound was obtained:

EXAMPLE 17 6-benzyloxy-3-cyclopentyl-1-(4-benzyloxyphenyl)-1H-indazole

(66%).

¹H-RMN (DMSO d₆): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 3.88 (s, 3H), 5.15(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.25-7.58 (m, 5H), 7.65 (d, 1H).

Using the same procedure but replacing cyclopentyl(4-benzyloxy-2-fluorophenyl)methanone by cyclohexyl(4-benzyloxy-2-fluorophenyl)methanone and hydrazine hydrate bymethylhydrazine or benzylhydrazine, the following compound wererespectively obtained:

EXAMPLE 18 6-benzyloxy-3-cyclohexyl-1-methyl-1H-indazole

(66%).

¹H-RMN (DMSO d₆): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 3.88 (s, 3H), 5.15(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.25-7.58 (m, 5H), 7.65 (d, 1H).

EXAMPLE 19 1-benzyl-6-benzyloxy-3-cyclohexyl-1H-indazole

(76%).

¹H-RMN (DMSO d₆): 1.15-2.05 (m, 10H), 2.95 (dt, 1H), 5.10 (s, 2H), 5.15(s, 2H), 6.75 (dd, 1H), 7.12 (d, 1H), 7.15-7.65 (m, 10H), 7.65 (d, 1H).

EXAMPLE 20Tertio-butyl-6-benzyloxy-3-cyclohexyl-1H-indazole-1-carboxylate

At 0° C. di-tert-butyldicarbonate (36.38 g, 0.166 mol) in acetonitrile(340 ml) was added on a mixture of 6-benzyloxy-3-cyclohexyl-1H-indazole(42.50 g, 0.138 mol), TEA (22 ml, 0.152 mol), acetonitrile (460 ml) andDMAP (3.40 g, 0.027 mol).

The mixture was stirred at room temperature overnight, then concentratedunder vacuum, diluted with ethyl acetate and washed with water acidifiedwith HCl 2N to pH 2. The mixture was dried over Na₂SO₄, filtered anddiluted in diisopropyl ether, the expected product crystallized (44.50g, yield 79%).

¹H-NMR (DMSO d₆): 1.15-2.05 (m, 19H), 3.00 (m, 1H), 5.19 (s, 2H), 7.03(dd, 1H), 7.25-7.45 (m, 5H), 7.69 (d, 1H), 7.78 (d, 2H).

EXAMPLE 216-benzyloxy-3-cyclopentyl-1-(2-piperidin-1-yl-ethyl)-1H-indazole

6-benzyloxy-3-cyclopentyl-1H-indazole was heated for 1 hour with NaOH(1.64 g, 41 mmol) and 1-(2-chloroethyl)piperidine in EtOH (60 ml) at 40°C. The reaction was followed by TLC (toluene/dioxane: 7/3), and whencompleted, the mixture was cooled to room temperature. The mixture wasquenched by NH₄Cl, extracted with AcOEt, dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by flash chromatography(toluene/1,4-dioxane 7/3) gave the expected product (600 mg, 8% assolid).

¹H-RMN (DMSO d₆): 1.40-2.40 (m, 14H), 2.50-2.80 (m, 2H), 3.10-3.60 (m,5H), 4.30 (t, 2H), 5.15 (s, 2H), 6.70 (dd, 1H), 7.10 (d, 1H), 7.40 (m,5H), 7.60 (d, 1H).

Using the same procedure but replacing 1-(2-chloroethyl)piperidine by4-bromobenzylbromide, the following compound was obtained:

EXAMPLE 22 6-benzyloxy-1-(4-bromobenzyl)-3-cyclopentyl-1H-indazole

¹H-RMN (DMSO d₆): 1.50-2.20 (m, 8H), 3.38 (m, 1H), 5.15 (s, 2H), 5.50(s, 2H), 6.78 (dd, 1H), 7.05-7.55 (m, 10H), 7.60 (d, 1H).

EXAMPLE 23 3-cyclopentyl-1H-indazol-6-ol

A mixture of 6-benzyloxy-3-cyclopentyl-1H-indazole (13 g, 0.102 mol),Pd/C (5%, 0.65 g) and PtO₂ (catalytic amount) in ethanol (130 ml) wasstirred at room temperature under hydrogen. The reaction was followed byTLC (heptane/EtOAc 50/50). When completed, the mixture was filtered onCelite® and concentrated under vacuum. Crystallization fromCH₂Cl₂/pentane gave 7.2 g of white crystals (85%). mp 175° C.

¹H-NMR (DMSO, d₆): 1.40-2.20 (m, 8H), 3.35 (m, 1H), 6.55 (dd, 1H), 6.68(d, 1H), 7.50 (d, 1H), 9.45 (s, 1H), 12.05 (s, 1H).

Using the same procedure but replacing6-benzyloxy-3-cyclopentyl-1H-indazole by:

-   6-benzyloxy-3-cyclohexyl-1H-indazole-   6-benzyloxy-3-cyclohexyl-1-methyl-1H-indazole-   6-benzyloxy-3-cyclopentyl-1-(4-benzyloxyphenyl)-1H-indazole-   6-benzyloxy-3-cyclopentyl-1-(2-piperidin-1-yl-ethyl)-1H-indazole-   6-benzyloxy-1-(4-bromobenzyl)-3-cyclopentyl-1H-indazole-   1-benzyl-6-benzyloxy-3-cyclopentyl-1H-indazole-   Tertio-butyl-6-benzyloxy-3-cyclohexyl-1H-indazole-1-carboxylate    the following compounds were respectively obtained:

EXAMPLE 24 3-cyclohexyl-1H-indazol-6-ol

(85%). mp 147° C.

¹H-RMN (DMSO d₆): 1.10-2.10 (m, 10H), 2.90 (m, 1H), 6.55 (dd, 1H), 6.65(s, 1H), 7.50 (d, 1H), 9.45 (s, 1H), 12.05 (s, 1H).

EXAMPLE 25 3-cyclohexyl-1-methyl-1H-indazol-6-ol

(75%). mp 205° C.

¹H-RMN (DMSO d₆): 1.20-2.00 (m, 10H), 2.92 (dt, 1H), 3.80 (s, 3H), 6.60(dd, 1H), 6.68 (d, 1H), 7.55 (d, 1H), 9.58 (s, 1H).

EXAMPLE 26 3-cyclopentyl-1-(4-hydroxyphenyl)-1H-indazol-6-ol (54%). mp178° C.

¹H-RMN (DMSO d₆): 1.50-2.20 (m, 8H), 3.40 (t, 1H), 6.68 (dd, 1H), 6.83(d, 1H), 6.90 (d, 2H), 7.38 (d, 2H), 7.59 (d, 1H), 9.60 (s, 1H), 9.68(s, 1H).

EXAMPLE 27 3-cyclopentyl-1-(2-piperidin-1-yl-ethyl)-1H-indazol-6-ol,hydrochloride

(90%). mp 120° C.

¹H-NMR (DMSO d₆): 1.15-2.30 (m, 14H), 2.90 (m, 2H), 3.20-3.60 (m, 5H),4.68 (t, 2H), 6.70 (dd, 1H), 6.88 (d, 1H), 7.52 (d, 1H), 10.80 (s, 1H).

EXAMPLE 28 1-(4-bromobenzyl)-3-cyclopentyl-1H-indazol-6-ol

(90%). mp 147° C.

¹H-RMN (DMSO d₆): 1.45-2.30 (m, 8H), 3.35 (m, 1H), 5.40 (s, 2H), 6.60(d, 1H), 7.00-7.40 (m, 4H), 7.50 (d, 1H), 7.70 (s, 1H).

EXAMPLE 29 1-benzyl-3-cyclohexyl-1H-indazol-6-ol

(40%) mp 154° C.

¹H-NMR (CDCl₃): 1.10-2.40 (m, 10H), 3.03 (m, 1H), 5.40 (s, 2H), 5.70 (s,1H), 6.53 (d, 1H), 6.76 (dd, 1H), 7.00-7.35 (m, 5H), 7.60 (d, 1H).

EXAMPLE 30 Tertio-butyl-3-cyclohexyl-6-hydroxy-1H-indazole-1-carboxylate

(87%) mp 124° C.

¹H-NMR (DMSO d₆): 1.20-2.05 (m, 19H), 2.95 (m, 1H), 6.80 (dd, 1H), 7.40(d, 1H), 7.65 (d, 1H).

EXAMPLE 31 3-(1-adamantyl)-1H-indazol-6-ol, hydrochloride

A mixture of 3-(1-adamantyl)-6-methoxy-1H-indazole (210 mg, 0.75 mol) in40% HBr in acetic acid (10 ml) was heated overnight at 70° C. Themixture was poured onto ice and neutralised with a solution of NaHCO₃,then extracted with AcOEt, dried over Na₂SO₄, filtered and concentratedunder vacuum. Purification by flash chromatography (heptane/EtOAc 50/50)gave 200 mg of product. The solid was crystallised as HCl salt fromEt₂O. The crystals were filtered, washed with ether, and dried to give160 mg of salt (80%). mp 140° C.

¹H-NMR (DMSO d₆): 1.00-2.60 (m, 15H), 6.65 (d, 1H), 6.75 (s, 1H), 7.55(d, 1H).

Using the same procedure but replacing3-(1-adamantyl)-6-methoxy-1H-indazole by3-cycloheptyl-6-methoxy-1H-indazole, the following compound wasobtained:

EXAMPLE 32 3-cycloheptyl-1H-indazol-6-ol, hydrochloride

(60%). mp 95° C.

¹H-NMR (DMSO d₆): 1.20-2.00 (m, 12H), 3.1 (m, 1H), 6.62 (d, 1H), 6.64(s, 1H), 7.60 (d, 1H).

Preparation of 1H-Indazole Sulfonamides (9), (10), (11), (13) and (14)EXAMPLE 33 6-benzyloxy-3-cycloheptyl-1H-indazole-1-sulfonamide

Sulfamoyl chloride (2.9 g, 25 mmol) was added to a solution of6-benzyloxy-3-cycloheptyl-1H-indazole (6) (4 g, 1.75 mmol) inN,N-dimethylacetamide (40 ml) at 0° C. The mixture was stirred for 3 hat 0° C. After extraction with EtOAc, the organic layer was washed withNH₄Cl solution and brine. It was dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification by flash chromatography followedby crystallisation from EtOH gave 1.2 g of yellow crystals (24%).

¹H-NMR (DMSO d₆): 1.20-2.00 (m, 12H), 2.58 (m, 1H), 5.05 (s, 2H),6.65-7.00 (m, 1H), 7.20-7.50 (m, 6H), 7.92 (s, 1H), 8.55 (s, 2H).

Using the same procedure but replacing6-benzyloxy-3-cycloheptyl-1H-indazole by:

-   6-benzyloxy-3-cyclohexyl-1H-indazole-   3-cyclohexyl-1H-indazol-6-ol-   3-cyclohexyl-1-methyl-1H-indazol-6-ol-   1-benzyl-3-cyclohexyl-1H-indazol-6-01-   Tertio-butyl-6-benzyloxy-3-cyclohexyl-1H-indazole-1-carboxylate    the following compounds were respectively obtained:

EXAMPLE 34 6-benzyloxy-3-cyclohexyl-1H-indazole-1-sulfonamide (100%)

¹H-NMR (DMSO d₆): 1.10 to 2.10 (m, 10H), 3.05 (m, 1H), 5.15 (s, 2H),7.00 (dd, 1H), 7.25-7.60 (m, 6H), 7.80 (d, 1H), 8.35 (s, 2H).

EXAMPLE 35 1-(aminosulfonyl)-3-cyclohexyl-1H-indazol-6-yl-sulfamate

(40%). mp 213° C.

¹H-NMR (DMSO d₆): 1.20-2.10 (m, 10H), 3.13 (d, 1H), 7.25 (dd, 1H), 7.80(d, 1H), 8.00 (d, 1H), 8.10 (s, 2H), 8.50 (s, 2H).

EXAMPLE 36 3-cyclohexyl-1-methyl-1H-indazole-6-sulfonamide

(84%). mp 188° C.

¹H-NMR (DMSO d₆): 1.20-2.10 (m, 10H), 3.03 (m, 1H), 3.95 (s, 3H), 6.98(d, 1H), 7.45 (s, 1H), 7.85 (d, 1H), 8.00 (s, 2H).

EXAMPLE 37 1-benzyl-3-cyclohexyl-1H-indazol-6-yl-sulfamate

(85%) mp 188° C.

¹H-NMR (DMSO d₆): 1.10-2.10 (m, 10H), 3.04 (m, 1H), 5.55 (s, 2H), 7.05(d, 1H), 7.10 (m, 5H), 5.53 (s, 1H), 7.88 (d, 1H), 8.00 (s, 2H).

EXAMPLE 38Tertio-butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-1H-indazole-1-carboxylate

(46%) mp 128° C.

¹H-NMR (DMSO d₆): 1.20-2.10 (m, 19H), 3.10 (m, 1H), 7.23 (dd, 1H),7.90-8.05 (m, 2H), 8.11 (s, 2H).

Using the same procedure as in Example 21 but replacing6-benzyloxy-3-cyclopentyl-1H-indazole by:

-   6-benzyloxy-3-cycloheptyl-1H-indazol-1-sulfonamide-   6-benzyloxy-3-cyclohexyl-1H-indazol-1-sulfonamide    the following compounds were respectively obtained:

EXAMPLE 39 3-cycloheptyl-6-hydroxy-1H-indazole-1-sulfonamide

mp 155° C.

¹H-NMR (DMSO d₆): 1.20-2.00 (m, 1H), 2.60 (m, 1H), 6.70 (m, 2H), 6.90(s, 2H), 7.05 (m, 1H), 7.80 (s, 1H).

EXAMPLE 40 3-cyclohexyl-6-hydroxy-1H-indazole-1-sulfonamide

mp 162° C.

¹H-NMR (DMSO d₆): 1.10-2.10 (m, 10H), 3.00 (m, 1H), 6.78 (dd, 1H), 7.25(d, 1H), 7.68 (d, 1H), 8.22 (s, 2H), 10.05 (s, 1H).

EXAMPLE 41 3-cyclohexyl-1H-indazol-6-yl-sulfamate

A mixture oftertio-butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-1H-indazole-1-carboxylate(4.00 g, 10.12 mmol), water (10 ml), dioxan (30 ml) and few drops of HClconcentrated (30%) was stirred overnight and poured into water. Theprecipitate was collected by filtration to give the expected product.Crystallisation from toluene gave white crystals (1.25 g, 48%)

¹H-NMR (DMSO d₆): 1.10-2.10 (m, 10H), 3.04 (m, 1H), 6.95 (dd, 1H), 7.35(d, 1H), 7.83 (d, 1H), 7.96 (s, 2H).

Preparation of 3-bromomethyl-1H-indazoles (16), (17) and (18) EXAMPLE 421-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-methyl-1H-indazole

Di-tert-butyl-dicarbonate in acetonitrile was mixed at 0° C. with6-methoxy-3-methyl-1H-indazole (prepared following the proceduredescribed by F. Dennler, Tetrahedron, 22, 1966, 3131-3139) (26.27 g,0.162 mol), acetonitrile (200 ml), triethylamine (25 ml, 0.178 mol),DMAP (3.96 g, 0.0324 mol). The mixture was stirred at room temperatureovernight. Acetonitrile was concentrated under vacuum. The mixture wasextracted with ethylacetate and acidified at pH=2 with a solution ofconcentrated HCl, dried over Na₂SO₄, filtered and put indiisopropylether. 23.9 g of the expected product were obtained (assolid, 59%).

¹H-NMR (DMSO d₆): 1.60 (s, 9H), 2.44 (s, 3H), 3.85 (s, 3H), 6.95 (dd,1H), 7.50 (d, 1H), 7.65 (d, 1H).

EXAMPLE 431-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromo-methyl-1H-indazole

1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-methyl-1H-indazole (25.2 g,0.096 mol) was dissolved in CCl₄ and mixed with benzoyl peroxide (2.33g, 9.6 mmol). N-bromosuccinimide (NBS, 18.8 g, 0.109 mol) was slowlyadded to this mixture and heated under reflux overnight. The mixture wascooled at room temperature, filtered on Celite®, the filtrate wasconcentrated under vacuum and flashed with toluene. 10.5 g of theexpected product were obtained (32%, as oil).

¹H-NMR (DMSO d₆): 1.65 (s, 9H), 3.85 (s, 3H), 4.95 (s, 2H), 7.05 (dd,1H), 7.55 (s, 1H), 7.80 (d, 1H)

EXAMPLE 44{1-[(tert-butoxycarbonyl)oxy]-6-methoxy-1H-indazol-3-yl}acetonitrile

KCN (5.73 g, 88 mmol) in 23 ml of H₂O was added dropwise at 0° C. to1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromomethyl-1H-indazole (10.5g, 30.08 mmol) in 80 ml of ethanol and stirred at room temperature for 1h30. The mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over Na₂SO₄. Concentration andprecipitation in diisopropyl ether gave the expected product (4.42 g,50% as solid).

¹H-NMR (DMSO d6): 1.65 (s, 9H), 3.85 (s, 3H), 4.42 (s, 2H), 7.00 (d,1H), 7.50 (d, 1H), 7.75 (d, 1H).

Preparation of (1H-indazole-3-yl)acetonitrile (20), (21) and (22)EXAMPLE 452-(Z/E)-2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enenitrile

A solution of KOH at 40% in 3.5 ml of water and 7.1 ml ethanol was addeddropwise to p-anisaldehyde (2.06 ml, 16.9 mmol) and{1-[(tert-butoxycarbonyl)oxy]-6-methoxy-1H-indazol-3-yl}acetonitrile inethanol. When the reaction was complete, the mixture was filtered toobtain 3.53 g of the expected product (77% as solid).

¹H-NMR (DMSO d₆): 3.35 (s, 1H), 3.85 (s, 3H), 3.90 (s, 3H), 6.70-7.20(m, 4H), 7.85-8.15 (m, 4H).

Using the same procedure but replacing p-anisaldehyde by cyclohexanecarboxaldehyde, the following compound was obtained:

EXAMPLE 462-(Z/E)-3-cyclohexyl-2(6-methoxy-1H-indazol-3-yl)prop-2-enenitrile

(55.4%).

¹H-NMR (DMSO d₆): 1.20-1.80 (m, 10H), 2.60-2.75 (m, 1H), 3.80 (s, 3H),6.85 (dd, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.85 (d, 1H), 13.20 (s, 1H).

EXAMPLE 472-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)propanenitrile

To 2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enenitrile(3.53 g, 11.56 mmol) dissolved in ethanol was added portionwise NaBH₄(0.66 g, 17 mmol). The mixture was stirred at 70° C. overnight, thenpoured into water, acidified with concentrated HCl, extracted with ethylacetate. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The oil was precipitated in ethanol and diisopropyl etherto give the expected product (3.18 g, as a white powder 85.3%).

¹H-NMR (DMSO d₆): 3.56 (s, 3H), 3.60-3.80 (m, 2H), 3.85 (s, 3H), 4.26(t, 1H), 6.90-7.30 (m, 6H), 7.97 (d, 1H), 11.13 (s, 1H).

Using the same procedure but replacing2-(Z/E)-2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enenitrileby 2-(Z/E)-3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)prop-2-ene nitrile,the following compound was obtained:

EXAMPLE 48 3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile

(97.5%).

¹H-NMR (DMSO d₆): 0.85-2.45 (m, 13H), 3.80 (s, 3H), 4.65 (t, 1H), 6.75(dd, 1H), 6.90 (d, 1H), 7.65 (d, 1H), 12.85 (s, 1H).

EXAMPLE 49 3-cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)propanenitrile

3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile (1.61 g, 5.68mmol) was dissolved in CH₂Cl₂ and cooled with an ice bath. BBr₃/CH₂Cl₂1M (8.6 ml, 8.52 mmol) was added to this mixture, which was stirred at50° C., then poured onto saturated NaHCO₃ solution, extracted withethylacetate, dried over Na₂SO₄, filtered, concentrated under vacuum andpurified by flash chromatography (CH₂Cl₂/MeOH 98/2). Crystallisationfrom EtOH gave 780 mg of white crystals (51%). mp 175° C.

¹H-NMR (DMSO d₆): 0.80-2.05 (m, 13H), 4.65 (t, 1H), 6.70 (dd, 1H), 6.78(d, 1H), 7.60 (d, 1H), 9.70 (s, 1H), 12.60 (s, 1H).

Preparation of Propanamides (23)

Using the same procedure as in Example 27 but replacing3-(1-adamantyl)-6-methoxy-1H-indazole by:

-   2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)propanenitrile-   3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile    the following compounds were respectively obtained:

EXAMPLE 502-(1-acetyl-6-hydroxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)propanamide

(7.7%). mp=152° C.

¹H-NMR (DMSO d₆): 2.22 (s, 3H), 3.15 (q, 2H), 3.80 (s, 3H), 4.15 (m,1H), 6.68 (dd, 1H), 6.80 (d, 1H), 6.85-7.05 (m, 3H), 7.20 (d, 2H), 7.52(s, 1H), 7.80 (d, 1H), 12.53 (s, 1H).

EXAMPLE 51 3-cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)propanamide (34%).mp=199° C.

¹H-NMR (DMSO d₆): 0.70-2.10 (m, 13H), 3.90 (t, 1H), 6.55 (d, 1H), 6.75(s, 1H), 6.83 (s, 1H), 7.45 (s, 1H), 7.65 (d, 1H), 9.50 (s, 1H), 12.20(s, 1H).

Preparation of the 1H-pyrano[4,3,2-cd]indazoles (25), (26) and (27)EXAMPLE 52 7-methoxy-3-(4-methoxyphenyl)-1H-pyrano[4,3,2-cd]indazole

Using the same procedure as in Example 12 but replacing cyclopentyl(4-benzyloxy-2-fluorophenyl)methanone by5-chloro-7-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (preparedfollowing Kitagawa Chem Pharm Bull, 39, 1991, 2681), the expectedproduct was obtained (as a solid, 84%).

¹H-NMR (DMSO, d₆): 3.60 (s, 3H), 3.80 (s, 3H), 6.60 (d, 2H), 6.80 (d,2H), 7.10 (d, 1H), 7.30 (d, 1H), 7.80 (s, 1H).

Using the same procedure as in Example 49 but replacing3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile by7-methoxy-3-(4-methoxyphenyl)-1H-pyrano[4,3,2-cd]indazole, the followingcompounds were obtained:

EXAMPLE 53 3-(4-methoxy-phenyl)-1H-pyrano[4,3,2-cd]indazol-7-ol,hydrochloride

(26%). mp 255° C.

¹H-NMR (DMSO d₆): 3.55 (s, 3H), 6.63 (m, 4H), 7.05 (d, 2H), 8.05 (s,1H), 10.00 (s, 1H).

EXAMPLE 54 3-(4-hydroxy-phenyl)-1,1-pyrano[4,3,2-cd]indazol-7-ol,hydrochloride

(15%). mp 111° C.

¹H-NMR (DMSO d₆): 6.45 (s, 2H), 6.65 (d, 2H), 7.10 (d, 2H), 8.00 (s,1H), 10.00 (s, 1H).

Preparation of Oximes (28) and (30) EXAMPLE 551-adamantyl(2-chloro-4,6-dihydroxyphenyl)methanone

Boron tribromide 1M in CH₂Cl₂ was added to a solution of1-adamantyl-(2-chloro-4,6-dimethoxyphenyl)methanone (7 g, 21.0 mmoles)and CH₂Cl₂ (30 ml). The mixture was warmed overnight and then pouredinto water, extracted with ethyl acetate, dried over Na₂SO₄ andconcentrated under vacuum to give the expected product (1.9 g, 30%).

¹H-NMR (DMSO d₆): 1.00-1.90 (m, 15H), 6.25 (s, 1H), 6.30 (s, 1H), 10.00(s, 2H).

EXAMPLE 56 1-adamantyl(2-chloro-4,6-dihydroxyphenyl)methanone oxime

1-adamantyl-(2-chloro-4,6-dihydroxyphenyl)methanone (1.9 g, 6.2 mmoles),hydroxylamine hydrochloride (100 g) and pyridine (50 ml) were refluxedfor 4 h. The mixture was concentrated under vacuum, poured into water,extracted with ethyl acetate, washed with HCl 1N, dried over Na₂SO₄ andconcentrated under vacuum to give the crude product. Flashchromatography (AcOEt/toluene 3/7) gave the pure oxime (1 g as a solid,50%).

¹H-NMR (DMSO d₆): 1.50-2.00 (m, 15H), 6.24 (s, 1H), 6.28 (s, 1H).

Using the same procedure but replacing1-adamantyl-(2-chloro-4,6-dihydroxyphenyl)methanone by:

-   1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone-   cycloheptyl (4-benzyloxy-2-fluorophenyl)methanone    the following compounds were respectively obtained:

EXAMPLE 57 1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone oxime

(32%).

¹H-NMR (DMSO d₆): 1.20-2.20 (m, 15H), 5.10 (s, 2H), 6.80 (dt, 1H),6.90-7.17 (m, 2H), 7.20-7.60 (m, 5H), 10.55 (s, 1H).

EXAMPLE 58 cycloheptyl (4-benzyloxy-2-fluorophenyl)methanone oxime

(60%).

¹H-NMR (DMSO d₆): 1.10-2.00 (m, 12H), 2.10-2.20 (m, 1H), 5.10 (s, 2H),6.67-6.85 (m, 1H), 6.90-7.15 (m, 2H), 7.25-7.50 (m, 5H), 10.47 (s, 1H).

Preparation of Benzisoxazoles (31), (32) and (34) EXAMPLE 596-benzyloxy-3-cyclohexyl-1,2-benzisoxazole

A solution of hydroxylamine hydrochloride (11.7 g) in warm water (100ml) was poured into a mixture of cyclohexyl(4-benzyloxy-2-fluorophenyl)methanone (20.22 g, 64.7 mmol) and EtOH (54ml). A solution of sodium hydroxide (11.13 g, 0.278 mol) in water (54ml) was then added as rapidly as the reflux permitted. The reactionmixture was heated for 12 h and then most of the EtOH was removed bydistillation. To the residue was added a solution of potassium hydroxide(8.7 g, 0.155 mol) in water (54 ml). The mixture was refluxed for 2days, then cooled to about 6° C. and stirred vigorously. A white solidwas obtained, which was thoroughly washed with water and triturated withdiisopropyl ether. The benzisoxazole was obtained as a white powder(12.26 g, 62%) after filtration. mp 110° C.

¹H-NMR (DMSO d₆): 1.00-2.10 (m, 10H), 3.05 (m, 1H), 5.20 (s, 2H), 7.00(dd, 1H), 7.25-7.55 (m, 6H), 7.75 (d, 1H).

Using the same procedure but replacing cyclohexyl(4-benzyloxy-2-fluorophenyl)methanone bycyclohexyl-(2-fluoro-4-hydroxy-5-methoxyphenyl)methanone, the followingcompound was obtained:

EXAMPLE 60 3-cyclohexyl-6-hydroxy-5-methoxybenzisoxazole

(50.5%).

¹H-NMR (DMSO d₆): 1.20-2.10 (m, 10H), 3.05 (m, 1H), 3.85 (s, 3H), 6.95(s, 1H), 7.23 (s, 1H), 9.94 (s, 1H).

EXAMPLE 61 3-(1-adamantyl)-4-chloro-1,2-benzisoxazol-6-ol

Diethylazodicarboxylate (0.92 g, 1.7 eq) in THF (20 ml) was added to amixture of 1-adamantyl (2-chloro-4,6-dihydroxyphenyl)methanone oxime (1g, 3.1 mmoles), triphenyl phosphine (1.4 g, 1.7 eq) in THF (20 ml) at 0°C. The mixture was stirred 2 h at 0° C., poured into water, extractedwith ethylacetate, dried over Na₂SO₄ and concentrated under vacuum togive the crude product. Flash chromatography (AcOEt/toluene 1/9) andcrystallisation from EtOH yielded the expected product (230 mg, 23%). mp215° C.

¹H-NMR (CDCl₃): 1.50-2.10 (m, 15H), 6.23 (d, 1H), 6.32 (d, 1H).

EXAMPLE 62 3-(1-adamantyl)-6-benzyloxy-1,2-benzisoxazole

1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone oxime (2.3 mg, 6 mM)in DMF (30 ml) was added at 0° C. dropwise under N₂, to a stirredsuspension of NaH (0.61 g, 18 mM, 60% oil dispersion) in DMF (10 ml).After the complete addition, the reaction mixture was allowed to warm toroom temperature and poured into H₂O. The precipitate was collected byfiltration to give the expected product (2.06 g, 95%). mp 132° C.

¹H-NMR (DMSO d₆): 1.20-2.45 (m, 15H), 5.22 (s, 2H), 7.00 (d, 1H),7.30-7.60 (m, 6H), 7.72 (d, 1H).

Using the same procedure but replacing1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone oxime by cycloheptyl(4-benzyloxy-2-fluorophenyl)methanone oxime, the following compound wasobtained

EXAMPLE 63 6-benzyloxy-3-cycloheptyl-1,2-benzisoxazole

(90%). mp 80° C.

¹H-NMR (DMSO d₆): 1.30-2.20 (m, 12H), 3.25 (m, 1H), 5.21 (s, 2H), 7.00(dd, 1H), 7.25-7.60 (m, 6H), 7.75 (d, 1H).

Using the same procedure as in Example 23 but replacing6-benzyloxy-3-cyclopentyl-1H-indazole by:

-   3-(1-adamantyl)-6-benzyloxy-1,2-benzisoxazole-   6-benzyloxy-3-cycloheptyl-1,2-benzisoxazole-   6-benzyloxy-3-cyclohexyl-1,2-benzisoxazole    the following compounds were respectively obtained:

EXAMPLE 64 3-(1-adamantyl)-1,2-benzisoxazol-6-ol

(47.5%). mp 215° C.

¹H-NMR (DMSO d₆): 1.40-2.20 (m, 13H), 2.35 (s, 2H), 6.80 (dd, 1H), 6.92(d, 1H), 7.58 (d, 1H), 10.28 (s, 1H).

EXAMPLE 65 3-cycloheptyl-1,2-benzisoxazol-6-ol

(48%). mp 156° C.

¹H-NMR (DMSO d₆): 1.20-2.20 (m, 12H), 3.18 (m, 1H), 6.80 (d, 1H), 6.90(s, 1H), 7.65 (d, 1H), 10.25 (s, 1H).

EXAMPLE 66 3-cyclohexyl-1,2-benzisoxazol-6-ol

(37%). mp 181° C.

¹H-NMR (DMSO d₆): 1.10-2.10 (m, 10H), 3.02 (dt, 1H), 6.80 (dd, 1H), 6.90(s, 1H), 7.68 (d, 1H), 10.25 (s, 1H).

EXAMPLE 67 3-cyclohexyl-1,2-benzisoxazol-5,6-diol

Using the same procedure as in Example 49 but replacing3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile by3-cyclohexyl-6-hydroxy-5-methoxybenzisoxazole, the expected product wasobtained (48.4%). mp 177° C.

¹H-NMR (DMSO d₆): 1.20-2.05 (m, 10H), 3.05 (dt, 1H), 6.92 (s, 1H), 7.05(s, 1H), 9.55 (br s, 2H).

EXAMPLE 68 3-cyclohexyl-6-(2-piperidin-1-yl-ethoxy)-1,2-benzisoxazole

A mixture of 3-cyclohexyl-1,2-benzisoxazol-6-ol (2.69 g, 12 mmol),1-(2-chloroethyl)-piperidine hydrochloride (2.39 g, 13 mmol) and K₂CO₃(3.59 g, 26 mmol) in CH₃CN (30 ml) was heated at reflux for 3 h andstirred at room temperature overnight. The reaction mixture was pouredinto H₂O and extracted with EtOAc. The organic extract was washed withbrine, dried (Na₂SO₄) and concentrated to give a residue (3.78 g). Thisresidue was purified by flash chromatography (toluene/1,4-dioxane 8/2).Crystallisation from EtOH gave white crystals (0.53 g, 13.4%). mp 69° C.

¹H-NMR (DMSO d₆): 1.20-2.10 (m, 16H), 2.30-2.50 (m, 4H), 2.70 (t, 2H),2.95-3.05 (dt, 1H), 4.15 (t, 2H), 6.95 (dd, 1H), 7.25 (d, 1H), 7.75 (d,1H).

EXAMPLE 69 Trihydroxybenzoin

Resorcinol (100 g, 0.91 mol) and 4-hydroxyphenylacetic acid (138.4 g,0.91 mol) were dissolved into BF₃Et₂O (346 ml, 2.73 mol) under N₂. Themixture was stirred and heated at 50-60° C. After complete reaction, themixture was cooled to room temperature and poured into a large volume oficed water. The crude product was filtered off and dried to yieldtrihydroxybenzoin (70%). mp 211° C.

¹H-NMR (Acetone d₆): 4.12 (s, 2H), 6.78 (d, 2H), 6.91 (d, 1H), 7.13 (d,2H), 7.54-7.6 (m, 2H), 8.21 (s, 1H), 8.35 (s, 1H), 8.70 (s, 1H).

EXAMPLE 701-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone

To a cooled (0-5° C.) suspension of trihydroxybenzoin (100 g, 0.41 mol)and, as a catalyst, TsOH (0.062 g) in toluene (350 ml), a solution ofdihydropyran (DHP) (150 ml, 1.64 mol) was slowly added. The reactionmixture became homogenous and was stirred at room temperature for 1 h.Triethylamine was added and the solvent was evaporated under reducedpressure. The brown oil crystallized upon trituration with hotisopropanol (1.2 l) and a white solid was collected (182 g, 90%).

¹H-NMR (CDCl₃): 1.40-2.05 (m, 12H), 3.40-3.60 (m, 2H), 3.65-3.90 (m,2H), 4.05 (s, 2H), 5.30 (t, 1H), 5.40 (t, 1H), 6.46 (dd, 1H), 6.54 (d,1H), 6.94 (d, 2H), 7.10 (d, 2H), 7.68 (d, 1H), 12.52 (s, 1H).

EXAMPLE 711-[2-hydroxy-4-tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanoneoxime

A mixture of1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone(5 g, 12 mmol) and H₂NOH, HCl (8.59 g, 12.3 mmol) was stirred for 24 hin pyridine (65 ml) at room temperature. The reaction mixture was pouredinto a large volume of 99/1 H₂O/triethylamine and was then extractedwith EtOAc. The organic solution was washed with brine. After dryingover Na₂SO₄, EtOAc was evaporated. The residue was purified by flashcolumn chromatography (toluene/1,4-dioxane 90/1+TEA 1%) to provide acolorless oil (5.05 g, 97%).

¹H-NMR (DMSO d₆): 1.30-2.00 (m, 12H), 3.40-3.60 (m, 2H), 3.60-3.80 (m,2H), 4.12 (s, 2H), 5.38 (t, 1H), 5.45 (t, 1H), 6.48 (d, 1H), 6.50 (s,1H), 6.93 (d, 2H), 7.05-7.30 (m, 3H), 7.40 (d, 1H), 11.63 (s, 1H), 11.85(s, 1H).

EXAMPLE 726-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)benzyl]-1,2-benzisoxazole

Using the same procedure as in Example 61 but replacing1-adamantyl-(2-chloro-4,6-dihydroxyphenyl)methanone oxime by1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanoneoxime, the expected product was obtained (25%).

¹H-NMR (DMSO d₆): 1.40-2.10 (m, 12H), 3.40-3.85 (m, 4H), 4.25 (s, 2H),5.39 (s, 1H), 5.61 (s, 1H), 6.90-7.10 (m, 3H), 7.20-7.35 (m, 3H), 7.55(d, 1H)

EXAMPLE 73 3-(4-hydroxybenzyl)-1,2-benzisoxazol-6-ol

6-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)benzyl]-1,2-benzisoxazole(3.85 mmol) and paratoluenesulfonic acid (APTS, catalytic amount) weredissolved in methanol (20 ml). After reaction at 60-70° C. for 3 h, thereaction mixture was cooled to room temperature and poured into saturedNaHCO₃ and extracted with EtOAc. After washing (H₂O) and drying (MgSO₄),the extract was concentrated. The crude product was purified by flashchromatography (toluene/1,4-dioxane 8/2) and crystallised to give anoff-white crystal (0.58 g, 31%). mp 178° C.

¹H-NMR (DMSO d₆): 4.11 (s, 2H), 6.69 (d, 2H), 6.75 (dd, 1H), 6.90 (d,1H), 7.13 (d, 2H), 7.48 (d, 1H), 9.80 (s, 2H).

Preparation of Benzisoxazole Sulfamate (33)

Using the same procedure as in Example 33 but replacing6-benzyloxy-3-cycloheptyl-1H-indazole by:

-   3-(1-adamantyl)-1,2-benzisoxazol-6-ol-   3-cycloheptyl-1,2-benzisoxazol-6-ol-   3-cyclohexyl-1,2-benzisoxazol-6-01    the following compounds were respectively obtained:

EXAMPLE 74 3-(1-adamantyl)-1,2-benzisoxazol-6-yl sulfamate

(82%). mp 87° C.

¹H-NMR (DMSO d₆): 1.50-2.45 (m, 15H), 7.28 (dd, 1H), 7.63 (d, 1H), 7.96(d, 1H), 8.15 (s, 2H).

EXAMPLE 75 3-cycloheptyl-1,2-benzisoxazol-6-yl sulfamate

(54%). mp 82° C.

¹H-NMR (DMSO d₆): 1.40-2.10 (m, 12H), 3.32 (m, 1H), 7.30 (d, 1H), 7.60(d, 1H), 8.05 (d, 1H), 8.15 (s, 2H).

EXAMPLE 76 3-cyclohexyl-1,2-benzisoxazol-6-yl sulfamate

(46%). mp 145° C.

¹H-NMR (DMSO d₆): 1.20-2.20 (m, 10H), 3.15 (dt, 1H), 7.25 (dd, 1H), 7.62(d, 1H), 8.05 (d, 1H), 8.15 (s, 2H).

Preparation of Benzisoxazoles (36) (37) and (38) EXAMPLE 772-(Z/E)-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)prop-2-enenitrile

A solution of 40% KOH/H₂O (3 ml) and EtOH (4.8 ml) was added slowly to aheterogenous mixture of (6-methoxy-1,2-benzisoxazol-3-yl)acetonitrile(2.4 g, 12.7 mmoles), prepared following H. Uno (Chem. Pharm. Bull, 24(4), 632-643, 1976), 4-methoxybenzaldehyde (1.1 eq, 14 mmoles, 1.8 g)and EtOH (24 ml) at room temperature. The mixture was stirred at roomtemperature for 1 h and the precipitate was filtered under vacuum,washed with water and EtOH, to give pure2-(Z/E)-(6-methoxy-1,2-benzisoxazol-2-yl)-3-(4-methoxy-phenyl)-prop-2-enenitrile(3.15 g, 81%).

¹H-NMR (acetone d₆)=3.94 (s, 3H), 3.97 (s, 3H), 7.08 (dd, 1H), 7.15 (d,2H), 8.05-8.30 (m, 4H).

Using the same procedure but replacing 4-methoxybenzaldehyde by4-hydroxybenzaldehyde the following compound was obtained:

EXAMPLE 782-(Z/E)-3-(4-hydroxyphenyl)-2-(6-methoxy-1,2-benzisoxazol-3-yl)prop-2-enenitrile

(86%). mp >380° C.

¹H-NMR (DMSO d₆): 3.85 (s, 3H), 6.15 (d, 2H), 7.00 (d, 1H), 7.25 (s,1H), 7.70 (s, 3H), 8.00 (d, 1H).

EXAMPLE 792-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile

NaBH₄ (1.05 eq, 0.2 g, 5.15 mmoles) was added to an heterogenoussolution of2-(Z/E)-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxy-phenyl)prop-2-enenitrile(1.5 g, 4.9 mmoles) and EtOH (20 ml). The mixture was heated at 50° C.for 1 h, and acidified at pH 1 with HCl 1N, extracted with AcOEt, driedover Na₂SO₄ and concentrated under vacuum to give pure2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile(1.5 g, 100%).

¹H-NMR (CDCl₃)=3.35 (d, 2H), 3.80 (s, 3H), 3.90 (s, 3H), 4.45 (t, 1H),6.84 (d, 2H), 6.93 (dd, 1H), 7.02 (d, 1H), 7.04 (d, 2H), 7.50 (d, 1H).

EXAMPLE 802-(6-hydroxy-1,2-benzisoxazol-3-yl)-3-(4-hydroxyphenyl)propanenitrile

To a solution of2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile(1.5 g, 4.9 mmoles) in CH₂Cl₂ (100 ml) under N₂, was added BBr₃ 1M inCH₂Cl₂ (4 eq, 20 ml). The mixture was refluxed for 2 h, poured intowater and extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated under vacuum to give the crude product. Purification byflash chromatography (CH₂Cl₂/MeOH 98/2) and crystallisation from EtOHyielded the expected crystals (850 mg, 62%). mp 214° C.

¹H-NMR (DMSO d₆): 3.25 (m, 2H), 5.10 (t, 1H), 6.65 (d, 2H), 6.90 (d,1H), 7.00 (d, 2H), 7.06 (s, 1H), 7.70 (d, 1H), 9.35 (s, 1H), 10.50 (s,1H).

Using the same procedure as in Example 77 but replacing4-methoxybenzaldehyde by:

-   3-fluoro-4-methoxybenzaldehyde-   4-methoxy-2-methyl-benzaldehyde-   3-methoxy-benzaldehyde-   4-fluorobenzaldehyde-   cyclohexanal-   3,4-dimethoxybenzaldehyde    and then using the same procedures as described in Examples 79 and    80, the following compounds were respectively obtained:

EXAMPLE 812-(6-hydroxy-1,2-benzisoxazol-3-yl)-3-(3-fluoro-4-hydroxyphenyl)-propanenitrile

(56%). mp 201° C.

¹H-NMR (DMSO d₆): 3.25 (m, 2H), 5.15 (t, 1H), 6.70-7.20 (m, 5H), 7.72(d, 1H), 9.82 (s, 1H), 10.55 (s, 1H).

EXAMPLE 822-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-hydroxy-2-methylphenyl)-propanenitrile

(15%). mp 131° C.

¹H-NMR (acetone d₆): 2.11 (s, 3H), 3.28 (d, 2H), 3.80 (s, 3H), 4.72 (t,1H), 6.40-6.60 (m, 2H), 6.85 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 8.09(s, 1H).

EXAMPLE 832-(6-hydroxy-1,2-benzisoxazol-3-yl)-3-(3-hydroxyphenyl)propanenitrile

(20%).

¹H-NMR (acetone d₆): 3.25-3.60 (m, 2H), 4.90 (t, 1H), 6.60-7.25 (m, 6H),7.70 (d, 1H), 8.80 (br s, 1H).

EXAMPLE 842-(6-hydroxy-1,2-benzisoxazol-3-yl)-3-(4-fluorophenyl)propanenitrile

(35%). mp 152° C.

¹H-NMR (DMSO d₆): 2.40-2.70 (m, 2H), 3.95 (t, 1H), 4.25 (s, 1H),5.90-6.50 (m, 6H), 6.70 (d, 1H).

EXAMPLE 85 2-(6-hydroxy-2-benzisoxazol-3-yl)-3-cyclohexyl-propanenitrile

(63%). mp 111° C.

¹H-NMR (acetone d₆): 0.80-2.10 (m, 13H), 4.56 (dd, 1H), 6.90 (dd, 2H),7.02 (d, 1H), 7.67 (d, 1H), 9.38 (s, 1H).

EXAMPLE 862-(6-hydroxy-1,2-benzisoxazol-3-yl)-3-(3,4-dihydroxyphenyl)propanenitrile

(56%). mp 154° C.

¹H-NMR (DMSO d₆): 3.00-3.35 (m, 2H), 5.06 (t, 1H), 6.50 (dd, 1H),6.55-6.75 (m, 2H), 6.90 (dd, 1H), 7.00 (dd, 1H), 7.70 (d, 1H), 8.90 (brs, 1H).

Preparation of Benzisoxazoles (40) (41) (42) and (43) EXAMPLE 873-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole

3-methyl-1,2-benzisoxazol-6-ol (10 g, 67 mmoles) (prepared following M.A. Elkasaby, Indian J. Chem., 1987, 26, 620) and DMF (50 ml) were addedto a mixture of tert-butyldimethylsilyl chloride (1.05 eq, 10.6 g),imidazole (2.5 eq, 11.4 g) and DMF (100 ml) under N₂. The mixture wasthen stirred at room temperature for 1 h, poured into water andextracted with ethyl acetate, dried over Na₂SO₄, filtered andconcentrated under vacuum to give a crude product. Flash chromatography(AcOEt/Toluene 18/85 with 0.1% TEA) gave6-[(tert-butyl(dimethyl)silyl)oxy]-3-methyl-1,2-benzisoxazole (17.1 g,97%).

¹H-NMR (CDCl₃ d₁): 0.20 (s, 6H), 1.00 (s, 9H), 2.60 (s, 3H), 6.80 (dd,1H), 6.95 (d, 1H), 7.45 (d, 1H).

EXAMPLE 883-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole

NBS (12.7 g, 71.5 mmoles) and benzyl peroxide (1.6 g, 6.5 mmoles) wereadded to a mixture of3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (17.1 g,65 mmoles) and CCl₄ (200 ml). The mixture was refluxed overnight and theprecipitate was filtered, washed with CCl₄ and purified by flashchromatography (AcOEt/Toluene 1/9 with 0.1% TEA) to give

3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole(15.1 g, 68%).

¹H-NMR (CDCl₃ d₁): 0.25 (s, 6H), 1.00 (s, 9H), 4.57 (s, 2H), 6.88 (dd,1H), 7.02 (d, 1H), 7.55 (d, 1H).

EXAMPLE 893-(6-[(tert-butyl)silyl)oxy]-1,2-benzisoxazol-3-yl)-2-methoxyphenyl)propanenitrile

A solution of n-BuLi 2.0M in THF (9.7 mmoles) was slowly added to asolution of diisopropylamine (1.3 ml, 1.05 eq) and dry THF (10 ml) at−20° C. under N₂. The mixture was stirred for 30 min at −20° C., then4-methoxybenzonitrile (1.3 g, 8.8 mmoles) and dry THF (10 ml) wereslowly added at −78° C. The mixture was stirred for 30 min at −78° C.,then3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (3g, 8.8 mmoles) and dry THF (10 ml) were slowly added. The mixture wasthen stirred for 30 min at room temperature, poured into water,extracted with AcOEt, dried over Na₂SO₄, and purified by flashchromatography (AcOEt/Heptane 2/8 with 0.1% TEA) to give3-(6-[(tert-butyl)dimethylsilyl)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile(1 g, 28%).

¹H-NMR (CDCl₃ d₁): 0.20 (s, 6H), 1.00 (s, 9H), 3.25-3.65 (m, 2H),3.70-4.48 (t, 1H), 6.80-7.60 (m, 7H).

EXAMPLE 90 3-(6-hydroxy-1,2-benzisoxazol-3-yl)-2-(4methoxyphenyl)propanenitrile

A solution of nBu₄F 1N in THF was added to a mixture of3-(6-[(tert-butyl)silyl)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile(1.0 g, 2.45 mmoles) in dry THF (20 ml) at room temperature. The mixturewas then stirred at room temperature for 2 h and then poured into waterand extracted with ethyl acetate, dried over Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was purified by flashchromatography (AcOEt/Toluene 2/8) and crystallisation fromMeOH/cyclohexane yielded the expected product (210 mg, 30%).

¹H-NMR (DMSO d₆)=3.00-3.50 (m, 2H), 5.05 (t, 1H), 6.60 (d, 2H), 6.90(dd, 1H), 7.00 (d, 2H), 7.05 (s, 1H), 7.70 (d, 1H), 9.40 (s, 1H), 10.50(s, 1H).

Preparation of Benzisothiazoles (45) and (46) EXAMPLE 91 cyclohexyl(4-benzyloxy-2-benzylthiophenyl)methanone

A solution of phenylmethanethiol (2.35 ml, 20 mmoles) in THF (10 ml) wasslowly added to a mixture of potassium tert-butoxide (2.24 g, 20 mmoles)in THF (80 ml) under N₂ at room temperature. The mixture was stirred for15 min at room temperature and cyclohexyl(4-benzyloxy-2-fluorophenyl)methanone (6.5 g, 20 mmoles) in THF (10 ml)was slowly added. The mixture was heated for 2 h at 50° C. and pouredinto an aqueous solution of NH₄Cl, extracted with ethyl acetate, driedover Na₂SO₄ and concentrated under vacuum. The crude product waspurified by flash chromatography (Heptane/AcOEt 90/10 with 0.1% TEA) togive cyclohexyl (4-benzyloxy-2-benzylthiophenyl)methanone (8.3 g, 100%).

¹H-RMN (DMSO d₆): 1.00-1.85 (m, 10H), 3.10-3.30 (m, 1H), 4.15 (s, 2H),5.19 (s, 1H), 6.85 (dd, 1H), 7.05 (d, 1H), 7.15-7.60 (m, 10H), 7.90 (d,1H).

EXAMPLE 92 6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole

Sulfuryl chloride (1.77 ml, 2.2 mmoles) was slowly added to a solutionof cyclohexyl (4-benzyloxy-2-benzylthiophenyl)methanone (8.77 g, 21mmoles) in CH₂Cl₂ (80 ml) at 0° C. The mixture was stirred for 2 h atroom temperature and then concentrated under vacuum. THF (80 ml) wasadded to the mixture and then EtOH (80 ml) saturated with ammoniac wasslowly added at 0° C. The mixture was stirred overnight at roomtemperature, poured into water, extracted with ethyl acetate, dried overNa₂SO₄, filtered and concentrated under vacuum to give a crude product.Flash chromatography (heptane/AcOEt 98/2) gave6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole (3.55 g, 52%).

¹H-NMR (DMSO d₆): 1.10 to 2.00 (m, 10H), 3.25 (dt, 1H), 5.20 (s, 2H),7.12 (dd, 1H), 7.25 to 7.55 (m, 5H), 7.75 (d, 1H), 8.02 (d, 1H).

EXAMPLE 93 3-cyclohexyl-1,2-benzisothiazol-6-ol

A solution of boron tribromide 1M in CH₂Cl₂ (11.9 ml, 11.9 mmoles) wasslowly added to a solution of6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole (3.5 g, 10 mmoles) inCH₂Cl₂ (50 ml) at 0° C. The mixture was stirred at room temperature for15 min and poured into water. The precipitate was filtered, dried andcrystallised from EtOH to give pure 3-cyclohexyl-1,2-benzisothiazol-6-ol(940 mg, 40.3%). mp 190° C.

¹H-NMR (DMSO d₆): 1.10 to 2.10 (m, 10H), 3.20 (dt, 1H), 6.95 (dd, 1H),7.40 (d, 1H), 7.93 (d, 1H), 10.18 (s, 1H).

Using the same procedures as in Examples 91 to 93 but replacingcyclohexyl (4-benzyloxy-2-fluorophenyl)methanone by cyclopentyl(4-benzyloxy-2-fluorophenyl)methanone, the following compound wasobtained:

EXAMPLE 94 3-cyclopentyl-1,2-benzisothiazol-6-ol

mp 130° C.

¹H-NMR (DMSO d₆): 1.50 to 2.20 (m, 8H), 3.62 (m, 1H), 6.95 (dd, 1H),7.35 (d, 1H), 7.92 (d, 1H), 10.18 (s, 1H).

Preparation of Benzisothiazole Sulfamates (47) and (48) EXAMPLE 953-cyclohexyl-1,2-benzisothiazol-6-yl sulfamate

Sulfamoyl chloride (780 mg, 6.76 mmol) was added by portions to amixture of 3-cyclohexyl-1,2-benzisothiazol-6-ol (790 mg, 3.38 mmoles)and dimethylacetamide (15 ml) at 0° C. The mixture was stirred for 30min at 0° C. and then at room temperature overnight, poured into waterand extracted with ethyl acetate, dried over Na₂SO₄ and concentratedunder vacuum.

The crude product was purified by flash chromatography(Toluene/1,4-dioxan 9/1) and crystallised from EtOH/pentane to give theexpected product (620 mg, 59%). mp 150° C.

¹H-NMR (DMSO d₆): 1.20 to 2.05 (m, 10H), 3.30 (m, 1H), 7.40 (dd, 1H),8.10 (d, 1H), 8.15 (s, 2H), 8.25 (d, 1H).

Using the same procedure but replacing3-cyclohexyl-1,2-benzisothiazol-6-ol by3-cyclopentyl-1,2-benzisothiazol-6-ol, the following compound wasobtained:

EXAMPLE 96 3-cyclopentyl-1,2-benzisothiazol-6-yl sulfamate

mp 132° C.

¹H-NMR (DMSO d₆): 1.55 to 2.25 (m, 8H), 3.65-3.85 (m, 1H), 7.4 (dd, 1H),8.10 (s, 1H), 8.15 (s, 2H), 8.23 (d, 1H).

EXAMPLE 97 3-cyclohexyl-1,1-dioxido-1,2-benzisothiazol-6-yl sulfamate

Hydrogen peroxide (0.6 ml) was slowly added to a mixture of sulfamicacid, 3-cyclohexyl-1,2-benzisothiazol-6-yl-ester (1 g, 3.2 mmoles),trifluoroacetic acid (2 ml) and dichloromethane (20 ml) at roomtemperature. The mixture was then stirred for 2 h and then poured intowater. The precipitate was filtered and purified by flash chromatography(Toluene/1,4-dioxan 85/15) to give after crystallisation a solid (70 mg,6%). mp 170° C.

¹H-NMR (DMSO d₆): 1.10 to 2.20 (m, 10H), 7.25 (dd, 1H), 8.07 (d, 1H),8.25 (s, 1H), 8.43 (s, 1H).

Pharmacological Test Results

Subtype Estrogen Receptor Binding In Vitro

The method was derived from those described for rat uterus (Botella J.et al, J Endocrinol Invest, 1990, 13: 905-910) and human Ishikawa cell(Botella J., J Steroid Biochem Molec Biol, 1995, 55: 77-84) estrogenreceptors. Relative binding affinities (RBA) were determined bycompetitive radiometric binding assays, using purified full-lengthrecombinant human ERα and ERβ (PanVera, Madison, Wis.). Receptors wereincubated in Tris buffer (10 mM Tris, 2 mM DTT, 1 mg/BSA, 10% Glycerol,pH 7.5 with HCl) at 4° C. for 18-20 hours with 2 nM of [³H]-E₂ with orwithout increasing concentrations of test compound from 1 nM to 10 μM.Non-specific binding was measured in the presence of a 500-fold excessof unlabeled E₂. Separation of bound and free ³H-E₂ fractions wasachieved with dextran (0.25%) coated charcoal (2.5%) in Tris-EDTAbuffer. After shaking for a few seconds and centrifugation at 1500 g and4° C. for 10 minutes, 150 μl/well of Optiphase ‘Super Mix’ scintillationliquid was mixed with 50 μl of supernatant of each sample and theradioactivity was measured in a MicroBeta counter (Wallac, Turku,Finland). Data were evaluated by a sigmoidal dose-response curve (Prism,GraphPad Software Inc.) to estimate the concentration of competitor athalf-maximal specific binding (IC₅₀). RBA of each competitor wascalculated as the ratio of IC₅₀s of E₂ and competitor, and the RBA valuefor E₂ was arbitrarily set at 100%. The selectivity for ERα and ERβ wasobtained from the ratio R of the IC₅₀ for ERα to the IC₅₀ for ERβ foreach test compound.

TABLE 1 Estrogen Receptor α and β binding assays IC₅₀ (nM) RBA (%) R(IC₅₀s) Compound ER Mean ± S.E.M Mean ± S.E.M n α · β E₂ α  1.6 ± 0.1100.0± 59 0.8 β  2.1 ± 0.1 100.0± 59 Ex 23 α 1332.0 ± 267.8  0.2 ± 0.054 31.9 β 41.8 ± 7.1 10.4 ± 4.0  4 Ex 24 α 159.1 ± 23.7 1.2 ± 0.2 9 15.6β 10.2 ± 0.9 24.6 ± 4.3  9 Ex 31 α 119.0 ± 45.2 3.1 ± 0.8 4 3.3 β  36.2± 18.7 17.7 ± 5.1  4 Ex 35 α 2686.0 ± 593.0  0.1 ± 0.02 4 10.8 β 248.0 ±48.7 0.9 ± 0.1 4 Ex 40 α  1483.0 ± 1177.6  0.1 ± 0.02 5 7.9 β 187.6 ±34.0 1.0 ± 0.2 5 Ex 65 α 75.3 ± 5.4 2.5 ± 0.6 4 3.7 β 20.2 ± 4.2 13.2 ±3.1  4 Ex 66 α 260.0 ± 40.1 1.1 ± 0.2 4 5.8 β 44.6 ± 7.7 9.4 ± 3.1 4 Ex73 α 2912.3 ± 317.8 0.1 ± 0.0 3 6.0 β  484.8 ± 157.7 1.0 ± 0.3 4 Ex 80 α67.5 ± 5.0 3.4 ± 0.4 8 9.0 β  7.5 ± 0.7 43.0 ± 7.8  8 Ex 81 α 139.3 ±33.9 2.4 ± 0.7 4 9.7 β 14.4 ± 5.3 35.9 ± 14.0 4 Ex 84 α 2300.8 ± 445.6 0.1 ± 0.03 4 18.7 β 122.9 ± 25.9 2.5 ± 0.4 4 Ex 86 α 1894.0 ± 364.8 0.2 ± 0.03 4 14.1 β 134.8 ± 31.0 2.4 ± 0.4 4 Ex 93 α  88.6 ± 11.7 1.3 ±0.2 4 2.3 β 37.8 ± 5.4 5.1 ± 0.8 4 n = number of assaysEstrogenic and Anti-Estrogenic Activities In Vitro

The estrogenic and anti-estrogenic potentials of new compounds wereevaluated using the induction of alkaline phosphatase (APase) activity,an estrogen specific response in human endometrial adenocarcinomaIshikawa cells (Botella J., Steroid Biochem Molec Biol, 1995, 55: 77-84;Littlefield et al., Endocrinology, 1990, 127: 2757-2762). Ishikawa cellswere routinely grown as monolayers in Dulbecco's Modified Eagle's medium(DMEM) containing 4 mM Glutamax I and supplemented with 10% ofdecomplemented fetal calf serum (dFCS) and antibiotics. They weremaintained in a humidified atmosphere of 5% CO₂ and 95% air, at 37±0.1°C. Stocks were performed once a week to maintain continuous exponentialgrowth.

For studies, Ishikawa cells were plated into 96-well microplates. Thenext day, the medium was changed to a phenol red-free DMEM containing 5%dFCS stripped of endogenous estrogens by dextran coated charcoaltreatment. Twenty-four hours later, the medium was renewed and therelevant controls and test compounds, diluted appropriately inestrogen-free DMEM, were added either alone (estrogenic effect) or with10⁻⁸ M E₂ (anti-estrogenic effect) to the plated cells and incubated forfour days. For each compound, the tested concentrations ranged from10⁻¹² M to 10⁻⁵ M, and the final vehicle concentration did not exceed0.1%.

At the end of the incubation period, APase activity was assayed by amethod involving the hydrolysis of p-nitrophenyl phosphate top-nitrophenol at pH 9.8 and spectrophotometric determination of theproduct at 405 nm.

In brief, the microplates were first rinsed twice with cold phosphatebuffered solution and then placed at −80° C. for at least 15 minutes.After thawing at room temperature for 5-10 minutes, the plates were puton ice and 50 μl ice-cold solution containing 5 mM p-nitrophenylphosphate was added to each well. The plates were warmed to roomtemperature to allow for the development of the enzymatic reaction (t₀).After a 15 to 60 minute incubation period, the intensity of the yellowcolor generated by the production of p-nitrophenol was measured intoeach well at 405 nm using a microplate reader (Wallac, model 1420Victor²).

For each tested concentration, APase activity, reflected by absorbance,was first expressed as fold increase over control (FI) and then aspercentage of E₂ activity (10⁻⁸ M) chosen equal to 100%. Sigmoidaldose-response curves were plotted and EC₅₀ (estrogenic effect) and IC₅₀(anti-estrogenic effect) values were calculated for each compound.

TABLE 2 Estrogenic and anti-estrogenic activities In vitro Estrogenicactivity Anti-estrogenic activity Compound EC₅₀ (nM) ± S.E.M n IC₅₀ (nM)± S.E.M n E₂  0.1 ± 0.05 3 ± Ex 23 1695 ± 168 4 ND± 1 Ex 24 136.3 ± 1.2 4 ND± 1 Ex 31 30.8 ± 0.5 4 ND± 1 Ex 35 373.8 ± 43.0 3 ND± 1 Ex 40 131.9± 4.7  4 ND± 1 Ex 65 51.7 ± 6.2 4 ND± 1 Ex 66 220.6 ± 14.0 4 ND± 1 Ex 73ND± 4 ND± 1 Ex 80 147.3 ± 39.9 4 ND± 4 Ex 81 ND± 4 ND± 1 Ex 84 322.5 ±20   4 ND± 2 Ex 86 ND± 4 ND± 1 Ex 93 123.8 ± 8.9  4 —± 1 n = number ofassays; ND = not detected; — not determinedProliferative Activity In Vitro

The proliferative effect of the compounds of the invention was evaluatedon human breast cancer cell line MCF-7 by measuring the number of viablecells after 6 days of treatment.

MCF-7 cells were routinely cultured as monolayers in Dulbecco's modifiedEagle's medium (DMEM) containing 4 mM Glutamax and 4.5 g/l glucose andsupplemented with 5% (v/v) decomplemented fetal calf serum (dFCS) andantibiotics.

Cells were plated at 2.10⁶ cells/75 cm² flasks and incubated at 37° C.in a humidified atmosphere containing 5% CO₂. They were passaged onceweekly to maintain continuous exponential growth. Forty eight hoursbefore the start of an experiment, near-confluent cells were changed toa phenol red free DMEM containing 5% steroid-stripped dFCS by dextrancoated charcoal treatment (DCC-DMEM). On the day of the experiment,cells were harvested by brief exposure to trypsin and plated in DCC-DMEMin 96-well microplates at a density of 4.10³ cells/well. The next day,the medium was renewed and test compounds, diluted appropriately inestrogen-free DMEM, were added and incubated for six days. For eachcompound, the tested concentrations ranged from 10⁻¹² M to 10⁻⁵ M andthe final vehicle concentration did not exceed 0.1% (v/v). At the end ofthe incubation period, cell proliferation was evaluated by quantitationof the cellular ATP content which signals the presence of metabolicallyactive cells.

ATP Assay

The assay, based on the ATP-dependent luciferase reaction, enablesgeneration of a luminescent signal proportional to the amount of ATPpresent. As there is a linear relationship between the amount of ATP andthe number of viable cells present in culture, the luminescent signalallowed to precisely evaluate cell proliferation (Crouch, S. P. M. etal. J. Immunol. Meth., 1993, 160, 81; Kangas, L. et al. Med. Biol. 1984,62, 338; Petty, R. D. et al. 3. Biolum. Chethilum. 1995, 10, 29).

In brief, the microplates were inverted to discard the culture mediumand 100 μl of fresh medium was added into each well. The microplateswere equilibrated at room temperature for approximately 30 minutes. 100μl of luciferase reagent was added into each well and contents weremixed for 2 minutes to induce cell lysis. The plates were incubated atroom temperature for 10 minutes to stabilize luminescence signal.Luminescence was recorded using a microplate reader (Wallac, model 1420Victor²) and results were expressed as percentage of the controlluminescence. Sigmoidal dose-response curves were plotted and EC₅₀values were calculated for each compound in order to evaluate theirproliferative potency.

TABLE 3 Proliferative activities in MCF-7 cells Cell proliferationEffect at Effect at 10⁻⁸M (% 10⁻⁶M (% Compound EC₅₀ (nM) ± S.E.M n ofcontrol) of control) E₂ 0.01 ± 0   4 211.6 204.7 Ex 23 376.5 ± 70.1 381.7 175.7 Ex 24 18.5 ± 1.8 3 89.9 142.8 Ex 31  3.7 ± 0.7 4 138.8 146.3Ex 35  58.2 ± 15.0 4 94.4 162.6 Ex 40 11.5 ± 2.8 4 106.9 151.7 Ex 6527.6 ± 2.0 4 123.1 259.5 Ex 66 25.4 ± 4.0 4 100.3 148.7 Ex 73  365.1 ±126.1 4 94.2 133.7 Ex 80  45.2 ± 25.6 4 109.5 147.2 Ex 81  634.8 ± 284.94 86.8 117.3 Ex 84 77.9 ± 4.1 4 97.0 285.8 Ex 86 465.7 ± 34.0 4 85.6139.4 Ex 93 16.1 ± 2.6 4 115.8 155.8Estrogenic Activity In Vivo

Prepubescent female rats were orally treated at 3 mg/rat/day for 3 days.On the day following the last treatment, uteri were removed and wetweights were recorded.

The results are expressed as % of stimulation of uterus weight incomparison with vehicles.

The compounds of examples 23, 31, 35, 66, 73, 84, 86 and 93 exhibited amarked selectivity for the human recombinant estrogen receptor β and aweak estrogenic effect in alkaline phosphatase activity in the Ishikawacell model.

These compounds were accordingly selected to check their in vitroestrogenicity. The aim of this study was to test these compounds incomparison with tamoxifen (TAM), with an ERβ selective standard agonist:DPN or 2,3-bis-(4-hydroxyphenyl)propionitrile (Meyers M J, J Med Chem2001, 44; 24, 4230-4251) and with an ERα selective standard agonist: PPTor 1,3,5-tris-(4-hydroxyphenyl)-4-propyl-1H-pyrazole (Stauffer S R, JMed Chem 2000, 43; 4934-4947), when 17β-estradiol (E2) at 3 mg/rat/dayp.o. is taken as the standard reference.

TABLE 4 Estrogenic activity of in vitro selected compounds Compound %stimulation vs vehicle Number of animals DPN 358 8 E₂ 526 8 Ex 23 12 8Ex 24 101 8 Ex 31 468 6 Ex 35 38 8 Ex 40 41 8 Ex 65 84 8 Ex 66 31 8 Ex73 52 8 Ex 80 70 8 Ex 81 49 8 Ex 84 24 8 Ex 86 25 8 Ex 93 88 8 PPT 96 6TAM 206 8

These results show that the compound of Example 23 is a potent ligand toestrogen receptor beta, with a weak in vivo estrogenic activity afteroral administration.

Dose-Related Uterotrophic Activity In Vivo

Prepubescent female rats were orally treated with 0.3; 1; 3 or 10mg/rat/day for 3 days. On the day following the last treatment, uteriwere removed and wet weights were recorded.

The results are expressed as % of stimulation of uterus weight incomparison with vehicles. 17β-estradiol (E2) at 3 mg/rat/day p.o. istaken as the standard reference.

TABLE 5 Dose-related uterotrophic activity in vivo Dosage % stimulationvs Number of Compound (mg/rat/day) vehicle animals E₂ 3 333 8 Ex 23 0.3−13 8 Ex 23 1 −5 8 Ex 23 3 −4 8 Ex 23 10 20 8

The compound of example 23 has been selected as a potential goodcandidate for treating estrogenic dependent diseases because of the lackof uterotrophicity up to a 3 mg/animal/day dosage, after oraladministration.

Effect of Compounds on Hot Flush Model In Vivo

According to Berendsen et al. (Eur. J. Pharmacol., 2003, 482; 329-33),tail skin temperature of ovariectomized rats may serve as a useful toolfor selection of compounds that are of potential use in the treatment ofhot flushes in postmenopausal women. The aim of this study was toevaluate the effect of the compound of Example 23 over 4 days on tailskin temperature in ovariectomized rats. 17β-estradiol, the standardreference, was administered by oral route at 1 mg/rat/day over 13consecutive days (Watanabe N. et al, 2003). Twenty IOPS Wistar femalerats from Charles River France, weighing 176 to 200 g on arrival, wereused for the study. Rats were accommodated in groups of four instainless steel mesh cages. After implantation of telemetrictransmitters (TA10TA-F40, Data Sciences International) until the end ofthe study, they were housed in groups of two in macrolon cages andmaintained on a 14-10 hours light/dark cycle. Standard environmentalconditions for this species were regularly controlled. Animals wereallowed free access to a specific estrogen-free diet of Harlan Teklad2016 pellets from HARLAN. They were allowed free access to filtered andsoftened tap water. Water was dispensed ad libitum via automaticdeliveries in metallic cages and in plastic bottles in macrolon cages.Rats were then ovariectomized and left undisturbed for at least 2 weeks.After this hormonal rest period, tail skin temperature was monitoredduring the same period and animals were randomized into 3 groups basedon mean temperature. The first group was “ovariectomy control group”,the second group was “estradiol group” to confirm the estrogen activityon tail temperature and the third group was “Ex 23 group” to test theactivity of this product on temperature. Body weights were then recordedon the first day of treatment and at the end of study.

The Results are expressed as % of stimulation of uterus weight incomparison with vehicles. 17β-estradiol (E2) at 3 mg/rat/day is taken asthe standard reference.

TABLE 6 Effect of Ex 23 on tail skin temperature (TST) in ovariectomizedrats TST TST TST Variation Variation Variation day 1 vs day 4 vs day 7vs Dosage day 0 day 0 day 0 Compound (mg/rat/day) (C. °) (C. °) (C. °) nvehicle — −0.6 −0.6 −0.7 4 E₂ 3 −4.8 −3.5 −5.6 4 Ex 23 0.3 −0.8 −2.1−1.9 10

The compound of example 23 decreased tail skin temperature ofovariectomized rat, without deleterious side-effects on uteri, unlikeestradiol activity on body weight or uteri (as seen below).

TABLE 7 Effect of Ex 23 on body weight and uteri, after one weektreatment Uteri weight Body weights Dosage (% increase (% increaseCompound (mg/rat/day) vs vehicle) vs vehicle) n vehicle — — — 4 E₂ 3 273−10 4 Ex 23 0.3 −2.6 +4.4 10Effect of Compounds on Bone and Cardiovascular Parameters in Vivo

The ovariectomized rat is a mandatory model for preclinical evaluationof new compounds used for the prevention of bone loss (osteoporosis).Female Wistar-derived OFA strain rats from IFFA CREDO (France) wereovariectomized or sham operated as intact control. Upon arrival, theywere housed in metal hanging cages in groups of 3 or 4 per cage and hadad libitum access to food and water for one week. After a one weekacclimation period, daily dosing was carried out with the compound ofinterest or 17β-estradiol.

During the study, plasma samples were taken to allow lipid parameterassay: triglycerides, free cholesterol, total cholesterol, HDL, LDL,VLDL, apoliporotein A and B100; bone metabolism parameters such as: DPD,Ca²⁺, collagen type I and H C-telopeptide fragments; and urinary bonemarkers such as Ca²⁺, and inorganic phosphate. All assays were carriedout following the manufacturer's recommendations. To allow bone mineraldensity measurement of individual lumbar segments, lumbar highresolution or whole body dual energy X-ray absorptiometry procedureswere carried out during the study on isoflurane anesthetized animals.

Antidepressant Activity of Compounds

Antidepressant effect of estradiol was recently reported in studiesusing ER β KO mice model. In addition, ER β localization in dorsal raphenucleus area in rat has been described. The gold standard test forantidepressant potency of compound consist in the forced swimming test,in this experiment antidepressants could be distinguished frompsychostimulants which decreased immobility at doses which increasedgeneral activity. In order to investigate the putative antidepressantpotency of the compounds reported here, the forced swimming test wasperformed according to the following design. The animals were housed sixper cage under standard colony conditions, with a 12 h light/dark cycleand ad libitum food and water. They were allowed to acclimatize to thecolony for at least 7 days prior to any experimentation. Forsubcutaneous administration, the compound of Example 23 was dissolved inolive oil and diluted to the desired concentration on the day ofadministration. For positive control, intraperitoneal (i.p.) injectionof desipramine was done. Desipramine was dissolved in double-distilledwater (10 mg/kg). The experiments were conducted 30 min after thepositive control drug treatment (only for desipramine treatment). Othercompounds, ie: estradiol and the compound of Example 23 were dailyinjected subcutaneously in rats, during a 7 days period. Acquisitionwere performed on day 8 (24 h after the last administration of items)and day 9 (48 h after estradiol or compound 23 administration),respectively. Data acquired 24 hours after the last administrationconsisted in the “naïve animal group”, these animals had never beenpreviously tested in the device. Data acquired 48 hours after a lastadministration of compounds consisted in “trained animal group”.

TABLE 8 Effect of Ex 23 onto immobility duration in stress conditionsDosage Naïve animals Trained animals Compound (mg/rat/day) (s.) (s.) nvehicle — 133.7 ± 28.6 178.1 ± 25.5 11 desipramine 30 Not tested  2.6 ±1.5*** 11 E2 0.007  22.5 ± 7.1***  79.2 ± 23.0* 11 Ex 23 2.8  45.2 ±15.6* 160.7 ± 44.1 12 (acquisition during a 10 minutes test, items ordesipramine vs vehicle, p < 0.05, p < 0.001)

On the 8th, the forced swim test was performed. This study was carriedout in rats according to the methods described by Porsolt (Eur. J.Pharm., 1978). Briefly, rats were placed individually in glass cylinders(height: 40 cm, diameter: 18 cm) containing 25 cm of water at 25° C. Tenminutes later, rats were removed and dried before being returned totheir home cages. The animals were replaced in the cylinders 24 h later,and the procedure was repeated, and a 10-min observation period wasrecorded. The model was validated by desipramine activity found in thetest. Results shown the confirmation of the antidepressor potency ofestradiol, 24 h and 48 h after administration. the compound of Example23 exhibited a antidepressor activity when animals werefirst-in-the-test 24 h after administration, while in trained animalgroup 48 h after administration, the antidepressor potency of thecompound of Example 23 disappeared.

1. A compound of formula (I)

or an acid addition salt or a stereoisomeric form thereof, wherein: R₁is hydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, trifluoromethyl,—N═CR₅R₆, —SO₂NR₇R₈, phenyl, phenyl(C₁-C₃)alkyl or (C₁-C₃)alkylsubstituted by a saturated heterocyclic radical, wherein the phenyl isunsubstituted or substituted by at least one substituent selected fromthe group consisting of a hydroxyl, a halogen, a nitro, a cyano, a(C₁-C₃)alkyl, a (C₁-C₃)alkoxy and a trifluoromethyl; R₁ can also be asalt; R₂ and R₃ are each independently hydrogen or a hydroxyl, halogen,nitro, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy,trifluoromethyl, —NR₇R₈, —CONR₇R₈, —COR_(S) or —CO₂R₉ group; R₂ can alsobe a phenyl or a saturated or unsaturated heterocycle, wherein thephenyl is unsubstituted or substituted by at least one substituentselected from the group consisting of a hydroxyl, a halogen, a nitro, acyano, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a trifluoromethyl and asaturated heterocyclic radical; X is O, S, SO, SO₂ or NR₄; R₄ ishydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl,phenyl(C₁-C₃)alkyl, (C₁-C₃)alkyl substituted by a saturated heterocyclicradical, —COR₇, —CO₂R₇ or —SO₂NR₇R₈ group, wherein the phenyl isunsubstituted or substituted by at least one substituent selected fromthe group consisting of a hydroxyl, a halogen, a nitro, a cyano, a(C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a trifluoromethyl, a phenyl(C₁-C₃)alkyland a phenyl(C₁-C₃)alkoxy; Y is direct bond, O, S, SO, SO₂, NR₄, CO,—(CR₁₀R¹¹)_(n)— or —R₁₀C═CR₁₁—; R₅, R₆, R₇ and R₈ are each independentlyhydrogen or a (C₁-C₆)alkyl or (C₃-C₆)cycloalkyl group; R₉ is hydrogen, a(C₁-C₆)alkyl, a phenyl or a saturated or unsaturated heterocyclicradical, wherein the phenyl is unsubstituted or substituted by at leastone substituent selected from the group consisting of a hydroxyl, ahalogen, a nitro, a cyano, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, atrifluoromethyl and a saturated heterocyclic radical; R₁₀ and R₁₁ areeach independently hydrogen or a cyano, (C₁-C₆)alkyl, —CO-phenyl,—CO(unsaturated heterocyclic radical) or —CONR₇R₈ group, wherein thephenyl is unsubstituted or substituted by at least one substituentselected from the group consisting of a hydroxyl, a halogen, a nitro, acyano, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy and a trifluoromethyl; n is 1 or2; A is a (C₃-C₁₅)cycloalkyl or a (C₃-C₁₅)cycloalkene, wherein thecycloalkyl or the cycloalkene is unsubstituted or substituted by atleast one (C₁-C₆)alkyl; when X is NR₄, Y and R₂ together with theindazole ring bearing them can also form a 1H-pyrano[4,3,2-cd]indazole;provided that: 1/ when X is NR₄, where R₄ is H or (C₁-C₆)alkyl and R₁Ois 6-OCH₃, then Y is not CO; 2/ when X is O, R₁O is 6-OH or 6-OCH₃, Y isa direct bond and A is cyclopentyl, then (R₂,R₃) or (R₃,R₂) is differentfrom (H, Cl) in position 4,5; 3/ when X is O, R₁O is 6-OH, R₂ ishydrogen, and R₃ is 7-propyl, then Y-A is not a cyclopropyl or acyclohexylmethyl; 4/ X and Y do not simultaneously represent NH.
 2. Acompound according to claim 1, wherein R₁ is hydrogen, a (C₁-C₆)alkyl, aphenyl(C₁-C₃)alkyl, a (C₁-C₃)alkyl substituted by a saturatedheterocyclic radical or a —SO₂NR₇R₈ group.
 3. A compound according toclaim 1 or an acid addition of salt thereof, wherein R₂ is hydrogen,hydroxyl, (C₁-C₆)alkyl or halogen.
 4. A compound according to claim 1 oran acid addition salt thereof, wherein R₃ is hydrogen.
 5. A compoundaccording to claim 1 or an acid addition salt thereof, wherein Y is adirect bond.
 6. A compound according to claim 1 or an acid addition saltthereof, wherein A is a (C₃-C₁₅)cycloalkyl optionally substituted by atleast one (C₁-C₆)alkyl.
 7. A compound according to claim 1 or an acidaddition salt thereof, wherein R₁O is in position 6- of the ring.
 8. Acompound according to claim 1 or an acid addition salt thereof, wherein:R₁ is hydrogen or a —SO₂NR₇R₈ group in which R₇ and R₈ are eachindependently hydrogen or a (C₁-C₆)alkyl; R₂ is hydrogen; and A is a(C₃-C₁₂)cycloalkyl optionally substituted by 1 to 4 (C₁-C₆)alkyl.
 9. Acompound according to claim 1 or an acid addition salt thereof, wherein:X is NR₄; R₁ is hydrogen or a (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl or—SO₂NR₇R₈ group; R₂ and R₃ are each hydrogen; R₄ is hydrogen or a(C₁-C₆)alkyl, phenyl, phenyl(C₁-C₃)alkyl, (C₁-C₃)alkyl substituted by asaturated heterocyclic radical, —SO₂NR₇R₈ or —COR₉ group, where thephenyl is optionally substituted by at least one substituent selectedfrom the group consisting of a hydroxyl, a halogen and aphenyl(C₁-C₃)alkoxy; Y is a direct bond, —(CR₁₀R₁₁)_(n)— or —R₁₀C═CR₁₁;R₇ and R₈ are each independently hydrogen or a (C₁-C₆)alkyl; R₉ ishydrogen or a (C₁-C₆)alkyl; R₁₀ and R₁₁ are each indepentyl hydrogen,cyano or a —CONR₇R₈ group; n is 1 or 2; A is a (C₃-C₁₅)cycloalkyloptionally substituted by at least one (C₁-C₆)alkyl; and Y and R₂together with the indazole ring bearing them can also form a1H-pyrano[4,3,2-cd]indazole.
 10. A compound according to claim 1 or anacid addition salt thereof, wherein: X is O; R₁ is hydrogen or a(C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, (C₁-C₃)alkyl substituted by asaturated heterocyclic radical or —SO₂NR₇R₈ group; R₂ is hydrogen,halogen, hydroxyl or (C₁-C₆)alkoxy; R₃ is hydrogen; Y is a direct bond,—(CR₁₀R₁₁)_(n) or —CR₁₀═CR₁₁—; R₇ and R₈ are each independently hydrogenor (C₁-C₆)alkyl; R₁₀ and R₁₁ are each independently hydrogen or cyano; nis 1 or 2; and A is a (C₃-C₁₅)cycloalkyl optionally substituted by atleast one (C₁-C₆)alkyl.
 11. A compound according to claim 1 or an acidaddition salt thereof, wherein: X is S(O)_(m); R₁ is hydrogen or aphenyl(C₁-C₃)alkyl or —SO₂NR₇R₈ group; R₂ and R₃ are each hydrogen,hydroxyl or halogen; Y is a direct bond, —(CR₁₀R₁₁)_(n) or —CR₁₀═CR₁₁—;R₇ and R₈ are each indepentyl hydrogen or a (C₁-C₆)alkyl; R₁₀ and R₁₁are each indepentyl hydrogen or cyano; A is a (C₃-C₁₅)cycloalkyloptionally substituted by at least one (C₁-C₆)alkyl; and m is 0, 1 or 2.12. A pharmaceutical composition comprising (i) a compound according toclaim 1 or a pharmaceutically acceptable salt thereof and (ii) apharmaceutically acceptable excipient.